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Hensen EF, van Duinen N, Jansen JC, Corssmit EPM, Tops CMJ, Romijn JA, Vriends AHJT, van der Mey AGL, Cornelisse CJ, Devilee P, Bayley JP. High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands. Mutations in four genes encoding subunits or cofactors of succinate dehydrogenase (SDH) cause hereditary paraganglioma and pheochromocytoma syndromes. Mutations in SDHB and SDHD are generally the most common, whereas mutations in SDHC and SDHAF2 are far less frequently observed. A total of 1045 DNA samples from Dutch paraganglioma and pheochromocytoma patients and their relatives were analyzed for mutations of SDHB, SDHC, SDHD or SDHAF2. Mutations in these genes were identified in 690 cases, 239 of which were index cases. The vast majority of mutation carriers had a mutation in SDHD (87.1%). The second most commonly affected gene was SDHAF2 (6.7%). Mutations in SDHB were found in only 5.9% of samples, whereas SDHC mutations were found in 0.3% of samples. Remarkably, 69.1% of all carriers of a mutation in an SDH gene in the Netherlands can be attributed to a single founder mutation in SDHD, c.274G>T and p.Asp92Tyr. Moreover, 88.8% of all SDH mutation carriers carry one of just six Dutch founder mutations in SDHB, SDHD and SDHAF2. The dominance of SDHD mutations is unique to the Netherlands, contrasting with the higher prevalence of SDHB mutations found elsewhere. In addition, we found that most SDH mutation-related paragangliomas-pheochromocytomas in the Netherlands can be explained by only six founder mutations in SDHAF2, SDHB and SDHD. The findings underline the regional differences in the SDH mutation spectrum, differences that should be taken into account in the development of effective screening protocols. The results show the crucial role that demographic factors play in the frequency of gene mutations. [ABSTRACT FROM AUTHOR]

Heavy metal ions are a common source of water pollution. In this study, two novel membranes with biobased metal-organic frameworks (BioMOFs) embedded in a polyacrylonitrile matrix with tailored porosity were prepared via nonsolvent induced phase separation methods and designed to efficiently adsorb heavy metal ions from oligomineral water. Under optimized preparation conditions, stable membranes with high MOF loading up to 50 wt % and a cocontinuous sponge-like morphology and a high water permeability of 50-60 L m -2 h -1 bar -1 were obtained. The tortuous flow path in combination with a low water flow rate guarantees maximum contact time between the fluid and the MOFs, and thus a high heavy metal capture efficiency in a single pass. The performances of these BioMOF@PAN membranes were investigated in the dynamic regime for the simultaneous removal of Pb 2+ , Cd 2+ , and Hg 2+ heavy metals from aqueous environments in the presence of common interfering ions. The new composite adsorbing membranes are capable of reducing the concentration of heavy metal pollutants in a single pass and at much higher efficiency than previously reported membranes. The enhanced performance of the mixed matrix membranes is attributed to the presence of multiple recognition sites which densely decorate the BioMOF channels: (i) the thioether groups, deriving from the S -methyl-l-cysteine and ( S )-methionine amino acid residues, able to recognize and capture Pb 2+ and Hg 2+ ions and (ii) the oxygen atoms of the oxamate moieties, which preferentially interact with Cd 2+ ions, as revealed by single crystal X-ray diffraction. The flexibility of the pore environments allows these sites to work synergically for the simultaneous capture of different metal ions. The stability of the membranes for a potential regeneration process, a key-factor for the effective feasibility of the process in real life applications, was also evaluated and confirmed less than 1% capacity loss in each cycle.

Eagle syndrome is a bone disease where elongation of the styloid process leads to throat and neck pain, and in severe cases neurovascular symptoms such as syncope and neuralgia. The pathophysiology of Eagle syndrome is poorly understood with various theories having been proposed how this elongation is caused. To better understand the pathophysiology, we performed a work-up in 6 patients presenting with Eagle syndrome. Patients mainly presented with pain on turning the neck (100%), foreign body sensation (67%), tension in the neck (67%), and dysphagia (50%). The typical length of the styloid process ranges from 25 to 30 mm; however, [ 18 F]NaF (sodium fluoride) PET/CT showed elongated styloid processes with an average length of 52.1 ± 15.6 mm (mean ± SD) with increased turnover at the base of one of the styloid processes. The removed styloid processes were further examined by histology, micro-CT, quantitative backscatter electron imaging (qBEI), Fourier transform infrared spectroscopy (FTIR), and circularly polarized light imaging. Histology revealed one case of a fractured styloid process healing through callus formation and one case of pseudarthrosis. Bone mineral density and mineralization was similar in the styloid processes when compared to cortical bone samples derived from the mandibular bone of different patients. Circular polarized light microscopy showed a collagen orientation in the styloid process comparable to the cortical bone samples with a distinct separation of collagen structure between the mineralized structure and the surrounding soft tissue with FTIR analysis demonstrating a typical composition of bone. This altogether suggests that the elongated styloid processes in Eagle syndrome are mature bone, capable of endochondral repair, possibly growing from the base of the process through endochondral ossification, rather than being a form of secondary calcification of the stylohyoid ligament as previously postulated., Competing Interests: No authors have conflicts of interest to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

During the production and laying phases of hot-mixing asphalt (HMA), various volatile organic compounds (VOCs) and noxious gases such as H 2 S are released into the atmosphere. These emissions are a serious environmental problem, a risk to human health, and expose workers and residents to unfriendly odours. The aim of this study was the development of a fast and sensitive analytical method to detect the H 2 S emitted from hot bituminous binder that is generally used in the various stages of asphalt production, processing, handling and during road construction. The method consisted in the analysis of evolved H 2 S from a flask with molten bitumen, using nitrogen as a carrier gas to lead the volatile compounds into a residual gas analyser equipped with a quadrupole mass spectrometer. The analysis was performed following the H 2 S-specific signals at m / z 33 (HS + ) and at m / z 34 (H 2 S + ) in real time, directly on the sample without laborious and expensive pre-treatments and with short response times (<6 s). Calibration with a standard mixture of 1000 ppm of H 2 S in nitrogen allows semi-quantitative H 2 S detection. The sensitivity and rapidity of the method were evaluated by quenching the release of sulphur compounds with commercial odour-suppressing agents. Upon addition of 0.1% of additive in two minutes, the H 2 S signal drops about 80% in two minutes, confirming the good response of the method, even with a very complex matrix.

Purpose: Arytenoid adduction as an addition to medialisation thyroplasty is highly advocated by some surgeons in selected cases but deemed less necessary by others in patients with unilateral vocal fold paralysis. This study aims to evaluate the additional benefits on voice outcome of arytenoid adduction in patients with unilateral vocal fold paralysis undergoing medialisation thyroplasty using intra-operative voice measurements., Design/methods: A prospective study was conducted. Voice audio recordings were obtained at 4 moments; 1. direct prior to the start of surgery, 2. during surgery after medialisation thyroplasty, 3. during surgery after medialisation and arytenoid adduction, 3 months postoperative. At these same timepoints patients rated their own voice on a numeric rating scale between 0 and 10. The blinded recordings were rated by consensus in a team of experienced listeners, using the Grade of the GRBAS scale. Furthermore, the Voice Handicap Index was administered before and at 3 months after surgery., Results: Ten patients who underwent medialisation and arytenoid adduction at our tertiary referral hospital between 2021 and 2022, were included. One patient was excluded after surgery. The intraoperative measurements showed a Grade score of 1.4 preoperatively, improving to 1.2 after medialisation, 1.2 after medialisation and arytenoid adduction, and further improving to 0.4 at 3 months postoperative, which was a not statistically significant improvement (p = 0.2). The intraoperative subjective numeric rating scale showed a statistically significant improvement from 3.9 preoperatively, to 6.1 after medialisation, 7.1 after medialisation and arytenoid adduction and a 7.6 at 3 months postoperative (p = 0.001). The Voice Handicap Index total score showed a statistically significant improvement from 71 points before surgery to 13 at 3 months after surgery (p = 0.008)., Conclusions: Our study using intraoperative voice measurements indicate that the addition of arytenoid adduction to medialisation thyroplasty is a benefit in selected patients although more studies are needed due to the many limitations inherent to this field of investigation., (© 2024. The Author(s).)

(1) Background: NF2 -related schwannomatosis, characterized by the development of bilateral vestibular schwannomas, often necessitates varied treatment approaches. Bevacizumab, though widely utilized, demonstrates variable effectiveness on hearing and tumor growth. At the same time, (serious) adverse events have been frequently reported. (2) Methods: A single center retrospective study was conducted, on NF2 -related schwannomatosis patients treated with bevacizumab from 2013 to 2023, with the aim to assess treatment-related and clinical outcomes. Outcomes of interest comprised hearing, radiologic response, symptoms, and adverse events. (3) Results: Seventeen patients received 7.5 mg/kg bevacizumab for 7.1 months. Following treatment, 40% of the patients experienced hearing improvement, 53%, stable hearing, and 7%, hearing loss. Vestibular schwannoma regression occurred in 31%, and 69% remained stable. Further symptomatic improvement was reported by 41%, stable symptoms by 47%, and worsened symptoms by 12%. Treatment discontinuation due to adverse events was observed in 29% of cases. Hypertension (82%) and fatigue (29%) were most frequently reported, with no occurrences of grade 4/5 toxicities. (4) Conclusion: Supporting previous studies, bevacizumab demonstrated positive effects on hearing, tumor control, and symptoms in NF2 -related schwannomatosis, albeit with common adverse events. Therefore, careful consideration of an appropriate management strategy is warranted.

Objective: To review the literature on intratympanic gentamicin treatment as prehabilitation for patients undergoing surgery for a unilateral vestibular schwannoma., Data Sources: A systematic literature search was conducted up to March 2023 in Pubmed, Embase, Cochrane, Web of Science, Academic Search Premier, Google Scholar and Emcare databases., Review Methods: Articles on the effect of intratympanic gentamicin followed by vestibular schwannoma surgery were reviewed. Data on objective vestibular function and subjective outcomes were compiled in tables for analysis. Relevance and methodological quality were assessed with the methodological index for non-randomized tool., Results: A total of 281 articles were identified. After screening and exclusion of duplicates, 13 studies were reviewed for eligibility, of which 4 studies could be included in the review. The posturography test, the subjective visual horizontal test, and the optokinetic nystagmus test showed decreased vestibular function in the group of patients who received intratympanic gentamicin before microsurgery compared to the group of patients without gentamicin. Other objective tests did not show significant differences between patient groups. Subjective vestibular outcomes, as evaluated by questionnaires on quality of life and/or dizziness, did not seem to improve from intratympanic gentamicin pretreatment., Conclusion: Vestibular schwannoma patients who received intratympanic gentamicin before surgical resection of the tumor performed better in the posturography test, subjective visual horizontal test, and the optokinetic nystagmus test afterwards. However, studies that also evaluated subjective outcomes such as dizziness, anxiety, depression, and balance self-confidence did not show a positive effect of intratympanic gentamicin on the vestibular complaints and symptoms., (© 2023. The Author(s).)

Objective: Validation of automated 2-dimensional (2D) diameter measurements of vestibular schwannomas on magnetic resonance imaging (MRI)., Study Design: Retrospective validation study using 2 data sets containing MRIs of vestibular schwannoma patients., Setting: University Hospital in The Netherlands., Methods: Two data sets were used, 1 containing 1 scan per patient (n = 134) and the other containing at least 3 consecutive MRIs of 51 patients, all with contrast-enhanced T1 or high-resolution T2 sequences. 2D measurements of the maximal extrameatal diameters in the axial plane were automatically derived from a 3D-convolutional neural network compared to manual measurements by 2 human observers. Intra- and interobserver variabilities were calculated using the intraclass correlation coefficient (ICC), agreement on tumor progression using Cohen's kappa., Results: The human intra- and interobserver variability showed a high correlation (ICC: 0.98-0.99) and limits of agreement of 1.7 to 2.1 mm. Comparing the automated to human measurements resulted in ICC of 0.98 (95% confidence interval [CI]: 0.974; 0.987) and 0.97 (95% CI: 0.968; 0.984), with limits of agreement of 2.2 and 2.1 mm for diameters parallel and perpendicular to the posterior side of the temporal bone, respectively. There was satisfactory agreement on tumor progression between automated measurements and human observers (Cohen's κ = 0.77), better than the agreement between the human observers (Cohen's κ = 0.74)., Conclusion: Automated 2D diameter measurements and growth detection of vestibular schwannomas are at least as accurate as human 2D measurements. In clinical practice, measurements of the maximal extrameatal tumor (2D) diameters of vestibular schwannomas provide important complementary information to total tumor volume (3D) measurements. Combining both in an automated measurement algorithm facilitates clinical adoption., (© 2023 The Authors. Otolaryngology-Head and Neck Surgery published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Background: Elective neck irradiation (ENI) is performed in head and neck cancer patients treated with definitive (chemo)radiotherapy. The aim is to eradicate nodal metastases that are not detectable by pretreatment imaging techniques. It is conceivable that personalized neck irradiation can be performed guided by the results of sentinel lymph node biopsy (SLNB). It is expected that ENI can be omitted to one or both sides of the neck in 9 out of 10 patients, resulting in less radiation side effects with better quality of life., Methods/design: This is a multicenter randomized controlled trial aiming to compare safety and efficacy of treatment with SLNB guided neck irradiation versus standard bilateral ENI in 242 patients with cN0 squamous cell carcinoma of the oropharynx, larynx or hypopharynx for whom bilateral ENI is indicated. Patients randomized to the experimental-arm will undergo SLNB. Based on the histopathologic status of the SLNs, patients will receive no ENI (if all SLNs are negative), unilateral neck irradiation only (if a SLN is positive at one side of the neck) or bilateral neck irradiation (if SLNs are positive at both sides of the neck). Patients randomized to the control arm will not undergo SLNB but will receive standard bilateral ENI. The primary safety endpoint is the number of patients with recurrence in regional lymph nodes within 2 years after treatment. The primary efficacy endpoint is patient reported xerostomia-related quality of life at 6 months after treatment., Discussion: If this trial demonstrates that the experimental treatment is non-inferior to the standard treatment in terms of regional recurrence and is superior in terms of xerostomia-related quality of life, this will become the new standard of care., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

The synthesis and characterization of a novel film-forming organic cage and of its smaller analogue are here described. While the small cage produced single crystals suitable for X-ray diffraction studies, the large one was isolated as a dense film. Due to its remarkable film-forming properties, this latter cage could be solution processed into transparent thin-layer films and mechanically stable dense self-standing membranes of controllable thickness. Thanks to these peculiar features, the membranes were also successfully tested for gas permeation, reporting a behavior similar to that found with stiff glassy polymers such as polymers of intrinsic microporosity or polyimides. Given the growing interest in the development of molecular-based membranes, for example for separation technologies and functional coatings, the properties of this organic cage were investigated by thorough analysis of their structural, thermal, mechanical and gas transport properties, and by detailed atomistic simulations., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Objective: This study evaluates the natural course of hearing loss (HL) prior to treatment in patients with progressive tumors and an indication for active intervention. Evaluating this patient group specifically can put hearing outcomes after vestibular schwannoma therapy into an adequate context., Study Design: Retrospective cohort study., Setting: Tertiary referral center., Methods: Inclusion criteria comprised unilateral vestibular schwannomas prior to active treatment, with ≥2 mm extracanalicular (EC) tumor growth and ≥2 audiograms. We performed a comprehensive assessment of hearing using multiple outcome parameters including (the annual decrease in) pure-tone averages (PTAs; an average of 0.5, 1, 2, and 3 kHz). Predictors for HL were evaluated (patient age, tumor size/progression, follow-up duration, baseline hearing)., Results: At presentation, 86% of patients suffered from sensorineural HL on the affected side (≥20 dB PTA) with a median of 39 dB (interquartile rate [IQR]: 27-51 dB). The median follow-up duration was 21 months (IQR: 13-34 months), after which 58% (187/322) of patients experienced progressive HL (≥10 dB), with a median increase of 6.4 dB/year. At the last follow-up, the median PTA was 56 dB (IQR: 37-73). Median speech discrimination scores deteriorated from 90% (IQR: 70%-100%) to 65% (IQR: 35%-100%). Tumor progression (maximal EC diameter) was significantly correlated to the progression of sensorineural HL, corrected for follow-up (F(2,228) = 10.4, p < .001, R 2  = 8%)., Conclusion: The majority of patients (58%) with radiologically confirmed progressive vestibular schwannomas experience progressive sensorineural HL during observation. Tumor progression rate, EC tumor extension, and longer follow-up are factors associated with more sensorineural HL., (© 2023 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Objective  The aim of this study was to assess the ability to smile following a hypoglossal-facial nerve transfer (N12-N7). Design  This is a retrospective chart review. Setting  National tertiary referral center for skull base pathology. Participants  Seventeen patients. Main Outcome Measures  The ability to smile following an N12-N7 transfer was assessed by five medical doctors on photographs of the whole face and frontal, orbital, and oral segments. The (segmented) photographs were scored for the symmetry, asymmetry, and correct or incorrect assessment of the affected side. Results  Seventeen patients were analyzed by 5 assessors providing 85 assessments. The whole face at rest was judged symmetrical in 26% of the cases and mildly asymmetrical in 56%. Frontal, orbital, and oral segments were symmetrical in 63, 20, and 35%, respectively. The affected side was correctly identified in 76%. When smiling, the whole face was symmetrical in 6% and mildly asymmetric in 59%. The affected side was correctly identified in 94%. The frontal, orbital, and oral segments during smiling were symmetrical in 67, 15, and 6%, respectively. The affected side of the frontal, orbital, and buccal facial segments during smiling was correctly identified in 89, 89, and 96%, respectively. Interobserver variability with Fleiss' kappa analysis showed that the strength of the agreement during smile of the total face was good (0.771) Conclusion  Following an N12-N7 transfer, a good facial symmetry at rest can be achieved. During smiling, almost all patients showed asymmetry of the face, which was predominantly determined by the orbital and oral segments. To improve the ability to smile after an N12-N7 transfer, additional procedures are needed., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

An increasing number of high-performing gas separation membranes is reported almost on a daily basis, yet only a few of them have reached commercialisation while the rest are still considered pure research outcomes. This is often attributable to a rapid change in the performance of these separation systems over a relatively short time. A common approach to address this issue is the development of mixed matrix membranes (MMMs). These hybrid systems typically utilise either crystalline or amorphous additives, so-called fillers, which are incorporated into polymeric membranes at different loadings, with the aim to improve and stabilise the final gas separation performance. After a general introduction to the most relevant models to describe the transport properties in MMMs, this review intends to investigate and discuss the main advantages and disadvantages derived from the inclusion of fillers of different morphologies. Particular emphasis will be given to the study of the compatibility at the interface between the filler and the matrix created by the two different classes of additives, the inorganic and crystalline fillers vs. their organic and amorphous counterparts. It will conclude with a brief summary of the main findings.

Patients with germline SDHD pathogenic variants (encoding succinate dehydrogenase subunit D; ie, paraganglioma 1 syndrome) are predominantly affected by head and neck paragangliomas, which, in almost 20% of patients, might coexist with paragangliomas arising from other locations (eg, adrenal medulla, para-aortic, cardiac or thoracic, and pelvic). Given the higher risk of tumour multifocality and bilaterality for phaeochromocytomas and paragangliomas (PPGLs) because of SDHD pathogenic variants than for their sporadic and other genotypic counterparts, the management of patients with SDHD PPGLs is clinically complex in terms of imaging, treatment, and management options. Furthermore, locally aggressive disease can be discovered at a young age or late in the disease course, which presents challenges in balancing surgical intervention with various medical and radiotherapeutic approaches. The axiom-first, do no harm-should always be considered and an initial period of observation (ie, watchful waiting) is often appropriate to characterise tumour behaviour in patients with these pathogenic variants. These patients should be referred to specialised high-volume medical centres. This consensus guideline aims to help physicians with the clinical decision-making process when caring for patients with SDHD PPGLs., Competing Interests: Declaration of interests DT has received personal honoraria for lectures and consulting and support for meeting attendance from Advanced Accelerator Applications and Novartis. CL-L has received personal honoraria for lectures and support for meeting attendance from Ipsen. SN has received research grant to their institution from German Research Foundation. LA has received personal honoraria for lectures from Servier and Ipsen. ALE has received fees for consulting from WL Gore and fees for participation on an advisory board from Artivion. ML has received research grants to their institution from Arbor, Bristol Myers Squibb, Accuray, Biohaven, and Urogen; honoraria for research consulting from VBI Vaccines, InCephalo Therapeutics, Merck, Pyramid Bio, Insightec, Biohaven, Sanianoia, Hemispherian, Novocure, Noxxon, InCando, Century Therapeutics, and CraniUs; honoraria for non-research consulting from Stryker; is a shareholder of Egret Therapeutics; holds patents for the combination of immunotherapy and local chemotherapy to treat malignancies (10864180) and focused radiation to augment immune-based strategies against cancer (9132281); and is a member of the data and safety monitoring board of Cellularity. ELP has received fees for participation on an advisory board from Vysioneer. RTC has received personal honoraria for lectures from Novartis, support for meeting attendance from Ipsen, and serves as a board member for the Society for Endocrinology clinical committee and the UK and Ireland Neuroendocrine Tumour Society clinical committee. JKL has received honoraria for lectures from and is a consultant for Stryker. ERM has received fees for consulting and personal honoraria for lectures from MSD. NN has received an intramural research grant from the National Institutes of Health. NP-T has received research grants to their institution from Innervate, Clarity pharma; fees for consulting from Progenics, Lantheus, and Innervate Lifesciences. NP-T is a member of the data and safety monitoring board of Progenics and Lantheus, and serves as a board member for Society of Nuclear Medicine and Molecular Imaging. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

(1) Background: This study aimed to evaluate the efficacy and treatment-related toxicity of proton radiotherapy (PRT) for vestibular schwannoma (VS) in patients with neurofibromatosis type 2-related schwannomatosis (NF2). (2) Methods: Consecutive NF2 patients treated with PRT for VS between 2004 and 2016 were retrospectively evaluated, focusing on tumor volume, facial and trigeminal nerve function, hearing, tinnitus, vestibular symptoms, and the need for salvage therapy after PRT. (3) Results: Eight patients were included (median age 36 years, 50% female). Median follow-up was 71 months. Five (63%) patients received fractionated PRT and three (38%) received PRT radiosurgery for VS. Six patients (75%) received prior VS surgery; three also received bevacizumab. Six patients (75%) did not require salvage therapy after PRT. Two patients (25%) with residual hearing lost it after PRT, and six had already lost ipsilateral hearing prior to PRT. Tumor and treatment-related morbidity could be evaluated in six patients. Following PRT, conditions that occurred or worsened were: facial paresis in five (83%), trigeminal hypoesthesia in two (33%), tinnitus in two (33%), and vestibular symptoms in four patients (67%). (4) Conclusion: After PRT for VS, the majority of the NF2 patients in the cohort did not require additional therapy. Tumor and/or treatment-related cranial nerve deficits were common. This is at least partly explained by the use of PRT as a salvage treatment after surgery or bevacizumab, in the majority of cases. There remains the further opportunity to elucidate the efficacy and toxicity of proton radiotherapy as a primary treatment.

Objective: Vestibular schwannoma management aims to maintain optimal quality of life (QoL) while preventing severe sequelae of the tumor or its treatment. This study assessed long-term QoL of patients with vestibular schwannoma in relation to treatment modality and decisional regret., Study Design: A longitudinal study, in which clinical and QoL data were used that were cross-sectionally acquired in 2014 and again in 2020 from the same patient group., Setting: A tertiary expert center for vestibular schwannoma care in the Netherlands., Methods: QoL was measured by the Penn Acoustic Quality of Life (PANQOL) scale. Changes in time were assed using a linear mixed model. In addition, the Decision Regret Scale was analyzed., Results: Of 867 patients, 536 responded (62%), with a median follow-up of 11 years. All PANQOL subdomain scores remained stable over time and did not exceed minimal clinically important difference (MCID) levels. Time since treatment did not affect QoL. Patients had comparable average QoL scores and proportions of patients with changing QoL scores (ie, exceeding the MCID) over time, irrespective of the received initial treatment. Female patients and those who required salvage therapy (either by radiotherapy or surgery) reported a lower QoL. The latter patient group reported the highest decisional regret., Conclusion: On average, the long-term QoL of patients with vestibular schwannoma is comparable for patients under active surveillance and those who have received active treatment, and it remains stable over time. This suggests that, on average, preservation of QoL of patients with vestibular schwannoma is feasible when adequately managed., (© 2022 The Authors. Otolaryngology-Head and Neck Surgery published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Objective: To analyze the effect of dizziness-related symptoms on the long-term quality of life (QoL) of patients with unilateral vestibular schwannoma., Methods: In this cross-sectional study, patients with a unilateral vestibular schwannoma diagnosed between 2004 and 2013 completed a disease-specific QoL questionnaire (Penn Acoustic Neuroma Quality of Life [PANQOL]) and the Dizziness Handicap Inventory (DHI) in 2020. Linear regression was performed to assess the correlation between QoL and the DHI total score, and the scores of the DHI functional, emotional, and physical subdomains. Potential confounders such as age, sex, tumor size at baseline, and treatment modality (active surveillance, surgery, or radiotherapy) were included in the model., Results: In total, 287 of 479 patients (59%) experienced dizziness with a median follow-up of 10 years. The DHI total score was significantly associated with the PANQOL total score. On average, we found a reduction of 0.7 points on the PANQOL for each additional point on the DHI. The DHI emotional subdomain was the most prominent determinant of poorer QoL. Each point on the DHI emotional subscale was associated with a reduction of 1.3 on the PANQOL score. Treatment modality did not have a clinically relevant effect on dizziness-related QoL., Conclusions: Even mild dizziness can have a significant and clinically relevant effect on the QoL of patients with unilateral vestibular schwannoma in the long term. This holds true for all treatment modalities. Addressing the vestibular problems may improve QoL in vestibular schwannoma patients, and DHI subscale analysis may help tailor the optimal vestibular intervention., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of Otology & Neurotology, Inc.)

Background: Traditional genotype-phenotype correlations for the succinate dehydrogenase-complex II (SDH) genes link SDHB variants to thoracic-abdominal pheochromocytoma-paraganglioma (PPGL) and SDHD variants to head and neck paraganglioma (HNPGL). However, in a recent study we found strong and specific genotype-phenotype associations for SDHD variants. In the present study we zoom in on the genotype-phenotype associations of SDHB gene variants, considering the impact of individual gene variants on disease risk and risk of malignancy., Methods: We analysed two large independent data sets, including a total of 448 patients with PPGL and HNPGL, and studied the association of missense or truncating SDHB variants with tumour incidence, age of onset and malignancy risk using binomial testing and Kaplan-Meier analysis., Results: Compared with missense variants, truncating SDHB variants were significantly and consistently more common in patients with PPGL, by a 20 percentage point margin. Malignancy was also significantly more common in truncating versus missense variant carriers. No overall differences in age of PPGL onset were noted between carriers of the two variant types, although some individual variants may differ in certain cases. Missense variants were marginally over-represented among patients with HNPGL, but the difference was not statistically significant., Conclusion: SDHB truncating variants convey an elevated risk for development of both PPGL and malignancy compared with missense variants. These results further support earlier robust associations between truncating variants and PPGL, and also suggest that the two variant types differ in their impact on complex II function, with PPGL/HNPGL tissues displaying differing sensitivities to changes in complex II function., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The neuroendocrine tumours paraganglioma and pheochromocytoma (PPGLs) are commonly associated with succinate dehydrogenase (SDH) gene variants, but no human SDH-related PPGL-derived cell line has been developed to date. The aim of this study was to systematically explore practical issues related to the classical 2D-culture of SDH-related human paragangliomas and pheochromocytomas, with the ultimate goal of identifying a viable tumour-derived cell line. PPGL tumour tissue/cells (chromaffin cells) were cultured in a variety of media formulations and supplements. Tumour explants and dissociated primary tumour cells were cultured and stained with a range of antibodies to identify markers suitable for use in human PPGL culture. We cultured 62 PPGLs, including tumours with confirmed SDHB, SDHC and SDHD variants, as well as several metastatic tumours. Testing a wide range of basic cell culture media and supplements, we noted a marked decline in chromaffin cell numbers over a 4-8 week period but the persistence of small numbers of synaptophysin/tyrosine hydroxylase-positive chromaffin cells for up to 99 weeks. In cell culture, immunohistochemical staining for chromogranin A and neuron-specific enolase was generally negative in chromaffin cells, while staining for synaptophysin and tyrosine hydroxylase was generally positive. GFAP showed the most consistent staining of type II sustentacular cells. Of the media tested, low serum or serum-free media best sustained relative chromaffin cell numbers, while lactate enhanced the survival of synaptophysin-positive cells. Synaptophysin-positive PPGL tumour cells persist in culture for long periods but show little evidence of proliferation. Synaptophysin was the most consistent cell marker for chromaffin cells and GFAP the best marker for sustentacular cells in human PPGL cultures., Competing Interests: The authors have declared that no competing interests exist.

In this work, thin film composite (TFC) membranes were fabricated with the selective layer based on a blend of polyimide Matrimid ® 5218 and polymer of intrinsic microporosity (PIM) composed of Tröger's base, TB, and dimethylethanoanthracene units, PIM-EA(Me 2 )-TB. The TFCs were prepared with different ratios of the two polymers and the effect of the PIM content in the blend of the gas transport properties was studied for pure He, H 2 , O 2 , N 2 , CH 4 , and CO 2 using the well-known time lag method. The prepared TFC membranes were further characterized by IR spectroscopy and scanning electron microscopy (SEM). The role of the support properties for the TFC membrane preparation was analysed for four different commercial porous supports (Nanostone Water PV 350, Vladipor Fluoroplast 50, Synder PAN 30 kDa, and Sulzer PAN UF). The Sulzer PAN UF support with a relatively small pore size favoured the formation of a defect-free dense layer. All the TFC membranes supported on Sulzer PAN UF presented a synergistic enhancement in CO 2 permeance, and CO 2 /CH 4 and CO 2 /N 2 ideal selectivity. The permeance increased about two orders of magnitude with respect to neat Matrimid, up to ca. 100 GPU, the ideal CO 2 /CH 4 selectivity increased from approximately 10 to 14, and the CO 2 /N 2 selectivity from approximately 20 to 26 compared to the thick dense reference membrane of PIM-EA(Me 2 )-TB. The TFC membranes exhibited lower CO 2 permeances than expected on the basis of their thickness-most likely due to enhanced aging of thin films and to the low surface porosity of the support membrane, but a higher selectivity for the gas pairs CO 2 /N 2 , CO 2 /CH 4 , O 2 /N 2 , and H 2 /N 2 .

Two novel imide/imine-based organic cages have been prepared and studied as materials for the selective separation of CO 2 from N 2 and CH 4 under vacuum swing adsorption conditions. Gas adsorption on the new compounds showed selectivity for CO 2 over N 2 and CH 4 . The cages were also tested as fillers in mixed-matrix membranes for gas separation. Dense and robust membranes were obtained by loading the cages in either Matrimid® or PEEK-WC polymers. Improved gas-transport properties and selectivity for CO 2 were achieved compared to the neat polymer membranes., (© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Background: T4-classified squamous cell carcinoma (SCC) of external auditory canal (EAC) can potentially involve different anatomical structures, which could translate into different treatment strategies and survival outcomes within one classification. Our aim is to evaluate the clinical added value of T4-subclasses proposed by Lavieille and by Zanoletti., Methods: Retrospective data, including patients with primary operated cT4-classified EAC SCC, was obtained from 12 international hospitals. We subclassified according to the T4-subclasses. The treatment strategies, disease-free survival (DFS) and overall survival per subclass were calculated., Results: A total of 130 T4-classified EAC SCC were included. We found commonly used treatment strategies per subclass according to Lavieille and the DFS seems also to differ per subclass. Subclass according to Zanoletti showed comparable treatment strategies and survival outcomes per subclass., Conclusion: Our study suggests that the subclass according Lavieille might have added value in clinical practice to improve care of T4-classified EAC SCC., (© 2022 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Purpose: To develop automated vestibular schwannoma measurements on contrast-enhanced T1- and T2-weighted MRI scans., Materials and Methods: MRI data from 214 patients in 37 different centers were retrospectively analyzed between 2020 and 2021. Patients with hearing loss (134 positive for vestibular schwannoma [mean age ± SD, 54 years ± 12;64 men] and 80 negative for vestibular schwannoma) were randomly assigned to a training and validation set and to an independent test set. A convolutional neural network (CNN) was trained using fivefold cross-validation for two models (T1 and T2). Quantitative analysis, including Dice index, Hausdorff distance, surface-to-surface distance (S2S), and relative volume error, was used to compare the computer and the human delineations. An observer study was performed in which two experienced physicians evaluated both delineations., Results: The T1-weighted model showed state-of-the-art performance, with a mean S2S distance of less than 0.6 mm for the whole tumor and the intrameatal and extrameatal tumor parts. The whole tumor Dice index and Hausdorff distance were 0.92 and 2.1 mm in the independent test set, respectively. T2-weighted images had a mean S2S distance less than 0.6 mm for the whole tumor and the intrameatal and extrameatal tumor parts. The whole tumor Dice index and Hausdorff distance were 0.87 and 1.5 mm in the independent test set. The observer study indicated that the tool was similar to human delineations in 85%-92% of cases., Conclusion: The CNN model detected and delineated vestibular schwannomas accurately on contrast-enhanced T1- and T2-weighted MRI scans and distinguished the clinically relevant difference between intrameatal and extrameatal tumor parts. Keywords: MRI, Ear, Nose, and Throat, Skull Base, Segmentation, Convolutional Neural Network (CNN), Deep Learning Algorithms, Machine Learning Algorithms Supplemental material is available for this article . © RSNA, 2022., Competing Interests: Disclosures of conflicts of interest: O.M.N. No relevant relationships. Y.C. Support from the present article from the China Scholarship Council. Q.T. No relevant relationships. S.R.R. No relevant relationships. N.P.d.B. No relevant relationships. W.G. No relevant relationships. M.C.K. No relevant relationships. B.P.F.L. No relevant relationships. J.C.J. No relevant relationships. E.F.H. No relevant relationships. B.M.V. Institutional grants or contracts from Advanced Bionics and Cochlear. M.S. No relevant relationships., (© 2022 by the Radiological Society of North America, Inc.)

Numerous studies have shown the recovery of auditory function in mouse models of genetic hearing loss following AAV gene therapy, yet translation to the clinic has not yet been demonstrated. One limitation has been the lack of human inner ear cell lines or tissues for validating viral gene therapies. Cultured human inner ear tissue could help confirm viral tropism and efficacy for driving exogenous gene expression in targeted cell types, establish promoter efficacy and perhaps selectivity for targeted cells, confirm the expression of therapeutic constructs and the subcellular localization of therapeutic proteins, and address the potential cellular toxicity of vectors or exogenous constructs. To begin to address these questions, we developed an explant culture method using native human inner ear tissue excised at either fetal or adult stages. Inner ear sensory epithelia were cultured for four days and exposed to vectors encoding enhanced green fluorescent protein (eGFP). We focused on the synthetic AAV9-PHP.B capsid, which has been demonstrated to be efficient for driving eGFP expression in the sensory hair cells of mouse and non-human primate inner ears. We report that AAV9-PHP.B also drives eGFP expression in fetal cochlear hair cells and in fetal and adult vestibular hair cells in explants of human inner ear sensory epithelia, which suggests that both the experimental paradigm and the viral capsid may be valuable for translation to clinical application.

Purpose: The aim of this study is to compute and validate a statistical predictive model for the risk of recurrence, defined as regrowth of tumor necessitating salvage treatment, after translabyrinthine removal of vestibular schwannomas to individualize postoperative surveillance., Methods: The multivariable predictive model for risk of recurrence was based on retrospectively collected patient data between 1995 and 2017 at a tertiary referral center. To assess for internal validity of the prediction model tenfold cross-validation was performed. A 'low' calculated risk of recurrence in this study was set at < 1%, based on clinical criteria and expert opinion., Results: A total of 596 patients with 33 recurrences (5.5%) were included for analysis. The final prediction model consisted of the predictors 'age at time of surgery', 'preoperative tumor growth' and 'first postoperative MRI outcome'. The area under the receiver operating curve of the prediction model was 89%, with a C-index of 0.686 (95% CI 0.614-0.796) after cross-validation. The predicted probability for risk of recurrence was low (< 1%) in 373 patients (63%). The earliest recurrence in these low-risk patients was detected at 46 months after surgery., Conclusion: This study presents a well-performing prediction model for the risk of recurrence after translabyrinthine surgery for vestibular schwannoma. The prediction model can be used to tailor the postoperative surveillance to the estimated risk of recurrence of individual patients. It seems that especially in patients with an estimated low risk of recurrence, the interval between the first and second postoperative MRI can be safely prolonged., (© 2022. The Author(s).)

Background: Employment is an important factor in quality of life. For vestibular schwannoma (VS) patients, employment is not self-evident, because of the sequelae of the disease or its treatment and their effects on daily life., Objectives: This study assessed employment status, sick leave (absenteeism) and being less productive at work (presenteeism) in the long-term follow-up of VS patients, and evaluated the impact of treatment strategy (active surveillance, surgery or radiotherapy)., Methods: A cross-sectional survey study was performed in a tertiary university hospital in the Netherlands. Patients completed the iMTA-post productivity questionnaire (iPCQ). Employment status was compared to that of the general Dutch population. Employment, absenteeism and presenteeism were compared between patients under active surveillance, patients after radiotherapy and post-surgical patients., Result: In total 239 patients participated, of which 67% were employed at the time of the study. Only 14% had a disability pension, which was comparable to the age-matched general Dutch population. The proportion of patients with absenteeism was 8%, resulting in a 4% reduction of working hours. Presenteeism was reported by 14% of patients, resulting in a 2% reduction of working hours. The median number of working hours per week was 36, and since the diagnosis, these hours had been reduced by 6%. There were no significant differences between treatment modalities., Conclusion: On average, long-term employment status and working hours of VS patients are comparable to the age-matched general population. Treatment strategies do not seem to differentially impact on long-term employment of VS patients., (© 2021. The Author(s).)

Objective: To evaluate the short- and long-term voice outcomes after unilateral medialization thyroplasty (MT) and unilateral medialization thyroplasty with arytenoid adduction (MT + AA) in patients with unilateral vocal fold paralysis., Methods: Voice outcomes were assessed preoperatively, and postoperatively at 3 and 12 months according to a standardized protocol. Voice assessment was performed using Voice Handicap Index (VHI), GRBAS Grade, Maximum Phonation Time (MPT), s/z-ratio and subjective numeric rating scales on voice quality, effort, performance and influence on life., Results: Sixty-one patients were included (34 MT and 27 MT + AA). Significant pre- to postoperative improvements were seen in all voice outcome parameters. No significant differences in post-operative values were identified between the groups., Conclusion: Based on our findings, we conclude that patients with unilateral vocal fold paralysis who undergo MT and MT + AA achieve comparable and significant long time voice improvement, although voices do not completely normalize. We also conclude that this does not mean that AA is a superfluous procedure, but can indicate the accurate identification of patients in need of the additional AA procedure based on clinical parameters., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The purpose of this study was to evaluate short- and long-term outcome of injection augmentation with autologous adipose tissue (AAT) and calcium hydroxylapatite injection (CAHA) in patients with a unilateral vocal fold paralysis (UVFP)., Design/methods: A retrospective cohort study was performed in patients diagnosed with UVFP, who had received injection augmentation with AAT or CAHA. Multidimensional voice analysis was performed before, 3 and 12 months after injection. This analysis included patient self-assessment (Voice Handicap Index-30), perceptual (overall dysphonia grade according to the GRBAS scale), aerodynamic (MPT, s/z ratio) and acoustic (fundamental frequency, dynamic range) parameters. Effects were assessed using a linear mixed model analysis., Results: Forty-six patients were available for evaluation, with a total of 53 injection augmentations (AAT n = 39; CAHA n = 14). We found significant improvement of patient self-assessment and perceptive voice outcome at 3 months, which were maintained at 12 months. In the CAHA group, s/z ratio and dynamic range of extreme frequencies also improved significantly over time. No statistically significant differences were found between the two treatments (AAT vs. CAHA). No major complications were reported., Conclusion: This study, using a guide-line recommended panel of outcome parameters, shows a high success rate of injection augmentation with AAT or CAHA for patients with UVFP at 12 months with significant improvement in most voice outcome parameters, although voices do not completely normalize. There is no significant difference in outcome between the two materials., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background & Aims: Recently, novel inborn errors of metabolism were identified because of mutations in V-ATPase assembly factors TMEM199 and CCDC115. Patients are characterized by generalized protein glycosylation defects, hypercholesterolemia, and fatty liver disease. Here, we set out to characterize the lipid and fatty liver phenotype in human plasma, cell models, and a mouse model., Methods and Results: Patients with TMEM199 and CCDC115 mutations displayed hyperlipidemia, characterized by increased levels of lipoproteins in the very low density lipoprotein range. HepG2 hepatoma cells, in which the expression of TMEM199 and CCDC115 was silenced, and induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells from patients with TMEM199 mutations showed markedly increased secretion of apolipoprotein B (apoB) compared with controls. A mouse model for TMEM199 deficiency with a CRISPR/Cas9-mediated knock-in of the human A7E mutation had marked hepatic steatosis on chow diet. Plasma N-glycans were hypogalactosylated, consistent with the patient phenotype, but no clear plasma lipid abnormalities were observed in the mouse model. In the siTMEM199 and siCCDC115 HepG2 hepatocyte models, increased numbers and size of lipid droplets were observed, including abnormally large lipid droplets, which colocalized with lysosomes. Excessive de novo lipogenesis, failing oxidative capacity, and elevated lipid uptake were not observed. Further investigation of lysosomal function revealed impaired acidification combined with impaired autophagic capacity., Conclusions: Our data suggest that the hypercholesterolemia in TMEM199 and CCDC115 deficiency is due to increased secretion of apoB-containing particles. This may in turn be secondary to the hepatic steatosis observed in these patients as well as in the mouse model. Mechanistically, we observed impaired lysosomal function characterized by reduced acidification, autophagy, and increased lysosomal lipid accumulation. These findings could explain the hepatic steatosis seen in patients and highlight the importance of lipophagy in fatty liver disease. Because this pathway remains understudied and its regulation is largely untargeted, further exploration of this pathway may offer novel strategies for therapeutic interventions to reduce lipotoxicity in fatty liver disease., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Low-temperature electrolysis by using polymer electrolyte membranes (PEM) can play an important role in hydrogen energy transition. This work presents a study on the performance of a proton exchange membrane in the water electrolysis process at room temperature and atmospheric pressure. In the perspective of applications that need a device with small volume and low weight, a miniaturized electrolysis cell with a 36 cm 2 active area of PEM over a total surface area of 76 cm 2 of the device was used. H 2 and O 2 production rates, electrical power, energy efficiency, Faradaic efficiency and polarization curves were determined for all experiments. The effects of different parameters such as clamping pressure and materials of the electrodes on polarization phenomena were studied. The PEM used was a catalyst-coated membrane (Ir-Pt-Nafion™ 117 CCM). The maximum H 2 production was about 0.02 g min -1 with a current density of 1.1 A cm -2 and a current power about 280 W. Clamping pressure and the type of electrode materials strongly influence the activation and ohmic polarization phenomena. High clamping pressure and electrodes in titanium compared to carbon electrodes improve the cell performance, and this results in lower ohmic and activation resistances.

Middle ear adenomatous neuroendocrine tumours (MEANTs) are rare, unpredictable tumours. Although most MEANTs are characterized by a benign biological behaviour and indolent growth pattern, some studies have reported locally invasive and metastastic disease. Currently, the optimal management strategy for MEANTs remains subject of debate. The aim of this study is to review the literature on MEANTs with focus on its clinical characteristics, treatment strategies and outcome. A systematic review was conducted using PubMed, Embase and Cochrane databases. A total of 111 studies comprising 198 patients with MEANT were included. Treatment modalities comprised surgery (90%), surgery with adjuvant radiotherapy (9%) and palliative (chemo)radiotherapy in (1%). Local recurrence was observed in 25% of the patients and 7% of the patients developed metastasis, over a median period of 5.7 years (range 7 months - 32 years). Twelve of 13 patients (92%) who developed metastases had a local recurrence. Four patients (2%) died of MEANT: three due to distant metastases and one due to extensive local recurrence. Reliable histopathologic predictors of outcome could not be identified. These findings indicate that the clinical presentations of MEANT vary substantially, the overall recurrence rate is considerable and initial local tumour control is paramount. Because of the unpredictable clinical course, prolonged follow-up is warranted., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Membrane-based processes are taking a more and more prominent position in the search for sustainable and energy-efficient gas separation applications. It is known that the separation performance of pure polymers may significantly be improved by the dispersion of suitable filler materials in the polymer matrix, to produce so-called mixed matrix membranes. In the present work, four different organic cages were dispersed in the poly(ether ether ketone) with cardo group, PEEK-WC. The m -xylyl imine and furanyl imine-based fillers yielded mechanically robust and selective films after silicone coating. Instead, poor dispersion of p -xylyl imine and diphenyl imine cages did not allow the formation of selective films. The H 2 , He, O 2 , N 2 , CH 4 , and CO 2 pure gas permeability of the neat polymer and the MMMs were measured, and the effect of filler was compared with the maximum limits expected for infinitely permeable and impermeable fillers, according to the Maxwell model. Time lag measurements allowed the calculation of the diffusion coefficient and demonstrated that 20 wt % of furanyl imine cage strongly increased the diffusion coefficient of the bulkier gases and decreased the diffusion selectivity, whereas the m -xylyl imine cage slightly increased the diffusion coefficient and improved the size-selectivity. The performance and properties of the membranes were discussed in relation to their composition and morphology.

Cellulose acetate (CA) is an attractive membrane polymer for CO 2 capture market. However, its low CO 2 permeability hampers its application as part of a membrane for most relevant types of CO 2 containing feeds. This work investigates the enhancement of CA separation performance by incorporating ionic liquid-like pendants (1-methylimidazol, 1-methylpyrrolidine, and 2-hydroxyethyldimethylamine (HEDMA) on the CA backbone. These CA-based polyelectrolytes (PEs), synthesised by covalent grafting of cationic pendants with anion metathesis, were characterised by NMR, FTIR, DSC/TGA, and processed into thin-film composite membranes. The membrane performance in CO 2 /N 2 mixed-gas permeation experiments shows a decrease in CO 2 and N 2 permeability and an initial decrease and then gradual increase in CO 2 /N 2 selectivity with increasing HEDMA content. The amount of HEDMA attached to the CA backbone determines overall separation process in bifunctional PEs. This indicates that the hydroxy-substituted cationic pendants alter interactions between PEs network and permeating CO 2 molecules, suggesting possibilities for further improvements., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To identify predictors of tumor recurrence and postoperative facial nerve function after translabyrinthine surgery for unilateral vestibular schwannomas., Study Design: Retrospective study., Setting: Tertiary referral center., Patients: Between 1996 and 2017 a total of 596 patients with unilateral vestibular schwannoma underwent translabyrinthine surgery. Pre- and postoperative clinical status, radiological, and surgical findings were evaluated., Interventions: Translabyrinthine surgery., Main Outcome Measures: Potential predictors for tumor recurrence and facial nerve outcome were analyzed using Cox regression and ordinal logistic regression, respectively., Results: The extent of tumor removal was total in 32%, near-total in 58%, and subtotal in 10%. In 5.5% (33/596) of patients the tumor recurred. Subtotal tumor resection (p = 0.004, hazard ratios [HR] = 10.66), a young age (p = 0.008, HR = 0.96), and tumor progression preoperatively (p = 0.042, HR = 2.32) significantly increased the risk of recurrence, whereas tumor size or histologic composition did not. A good postoperative facial nerve function (House-Brackmann grade 1-2) was achieved in 85%. The risk of postoperative facial nerve paresis or paralysis increased with tumor size (p < 0.001, OR = 1.52), but was not associated with the extent of tumor removal, histologic composition, or patient demographics., Conclusions: Translabyrinthine surgery is an effective treatment for vestibular schwannoma, with a good local control rate and facial nerve outcome. The extent of tumor removal is a clinically relevant predictor for tumor recurrence, as are young patient age and preoperative tumor progression. A large preoperative tumor size is associated with a higher risk of postoperative facial nerve paresis or paralysis., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of Otology & Neurotology, Inc.)

Ionic liquids have attracted the attention of the industry and research community as versatile solvents with unique properties, such as ionic conductivity, low volatility, high solubility of gases and vapors, thermal stability, and the possibility to combine anions and cations to yield an almost endless list of different structures. These features open perspectives for numerous applications, such as the reaction medium for chemical synthesis, electrolytes for batteries, solvent for gas sorption processes, and also membranes for gas separation. In the search for better-performing membrane materials and membranes for gas and vapor separation, ionic liquids have been investigated extensively in the last decade and a half. This review gives a complete overview of the main developments in the field of ionic liquid membranes since their first introduction. It covers all different materials, membrane types, their preparation, pure and mixed gas transport properties, and examples of potential gas separation applications. Special systems will also be discussed, including facilitated transport membranes and mixed matrix membranes. The main strengths and weaknesses of the different membrane types will be discussed, subdividing them into supported ionic liquid membranes (SILMs), poly(ionic liquids) or polymerized ionic liquids (PILs), polymer/ionic liquid blends (physically or chemically cross-linked 'ion-gels'), and PIL/IL blends. Since membrane processes are advancing as an energy-efficient alternative to traditional separation processes, having shown promising results for complex new separation challenges like carbon capture as well, they may be the key to developing a more sustainable future society. In this light, this review presents the state-of-the-art of ionic liquid membranes, to analyze their potential in the gas separation processes of the future.

Context: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors in which altered central metabolism appears to be a major driver of tumorigenesis, and many PPGL genes encode proteins involved in the tricarboxylic acid (TCA) cycle., Objective/design: While about 40% of PPGL cases carry a variant in a known gene, many cases remain unexplained. In patients with unexplained PPGL showing clear evidence of a familial burden or multiple tumors, we aimed to identify causative factors using genetic analysis of patient DNA and functional analyses of identified DNA variants in patient tumor material and engineered cell lines., Patients and Setting: Patients with a likely familial cancer burden of pheochromocytomas and/or paragangliomas and under investigation in a clinical genetic and clinical research setting in university hospitals., Results: While investigating unexplained PPGL cases, we identified a novel variant, c.1151C>T, p.(Pro384Leu), in exon 14 of the gene encoding dihydrolipoamide S-succinyltransferase (DLST), a component of the multi-enzyme complex 2-oxoglutarate dehydrogenase. Targeted sequence analysis of further unexplained cases identified a patient carrying a tumor with compound heterozygous variants in DLST, consisting of a germline variant, c.1121G>A, p.(Gly374Glu), together with a somatic missense variant identified in tumor DNA, c.1147A>G, p.(Thr383Ala), both located in exon 14. Using a range of in silico and functional assays we show that these variants are predicted to be pathogenic, profoundly impact enzyme activity, and result in DNA hypermethylation., Conclusions: The identification and functional analysis of these DLST variants further validates DLST as an additional PPGL gene involved in the TCA cycle., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aims: Vacuolar H+-ATP complex (V-ATPase) is a multisubunit protein complex required for acidification of intracellular compartments. At least five different factors are known to be essential for its assembly in the endoplasmic reticulum (ER). Genetic defects in four of these V-ATPase assembly factors show overlapping clinical features, including steatotic liver disease and mild hypercholesterolemia. An exception is the assembly factor vacuolar ATPase assembly integral membrane protein (VMA21), whose X-linked mutations lead to autophagic myopathy., Approach and Results: Here, we report pathogenic variants in VMA21 in male patients with abnormal protein glycosylation that result in mild cholestasis, chronic elevation of aminotransferases, elevation of (low-density lipoprotein) cholesterol and steatosis in hepatocytes. We also show that the VMA21 variants lead to V-ATPase misassembly and dysfunction. As a consequence, lysosomal acidification and degradation of phagocytosed materials are impaired, causing lipid droplet (LD) accumulation in autolysosomes. Moreover, VMA21 deficiency triggers ER stress and sequestration of unesterified cholesterol in lysosomes, thereby activating the sterol response element-binding protein-mediated cholesterol synthesis pathways., Conclusions: Together, our data suggest that impaired lipophagy, ER stress, and increased cholesterol synthesis lead to LD accumulation and hepatic steatosis. V-ATPase assembly defects are thus a form of hereditary liver disease with implications for the pathogenesis of nonalcoholic fatty liver disease., (© 2020 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: Squamous cell carcinoma (SCC) of the external auditory canal (EAC) is a rare disease, which is commonly classified with the modified Pittsburgh classification. Our aim was to evaluate the predictive performance of this classification in relation to disease-free survival (DFS)., Methods: We examined retrospective data from a nationwide Dutch cohort study including patients with primary EAC SCC. These data were combined with individual patient data from the literature. Using the combined data, the predictive performances were calculated using the c-index., Results: A total of 381 patients were included, 294 for clinical and 281 for the pathological classification analyses. The c-indices of the clinical and the pathological modified Pittsburgh classification predicting DFS were 0.725 (0.668-0.782) and 0.729 (0.672-0.786), respectively., Conclusion: The predictive performance of the modified Pittsburgh classification system as such appears to be acceptable to predict the DFS of EAC SCC. Other factors need to be added to a future model to improve the predicted performance., (© 2020 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Global warming by greenhouse gas emissions is one of the main threats of our modern society, and efficient CO 2 capture processes are needed to solve this problem. Membrane separation processes have been identified among the most promising technologies for CO 2 capture, and these require the development of highly efficient membrane materials which, in turn, requires detailed understanding of their operation mechanism. In the last decades, molecular modeling studies have become an extremely powerful tool to understand and anticipate the gas transport properties of polymeric membranes. This work presents a study on the correlation of the structural features of different membrane materials, analyzed by means of molecular dynamics simulation, and their gas diffusivity/selectivity. We propose a simplified method to determine the void size distribution via an automatic image recognition tool, along with a consolidated Connolly probe sensing of space, without the need of demanding computational procedures. Based on a picture of the void shape and width, automatic image recognition tests the dimensions of the void elements, reducing them to ellipses. Comparison of the minor axis of the obtained ellipses with the diameters of the gases yields a qualitative estimation of non-accessible paths in the geometrical arrangement of polymeric chains. A second tool, the Connolly probe sensing of space, gives more details on the complexity of voids. The combination of the two proposed tools can be used for a qualitative and rapid screening of material models and for an estimation of the trend in their diffusivity selectivity. The main differences in the structural features of three different classes of polymers are investigated in this work (glassy polymers, superglassy perfluoropolymers and high free volume polymers of intrinsic microporosity), and the results show how the proposed computationally less demanding analysis can be linked with their selectivities.

Congenital disorders of glycosylation (CDG) are a rapidly expanding group of rare genetic defects in glycosylation. In a novel CDG subgroup of vacuolar-ATPase (V-ATPase) assembly defects, various degrees of hepatic injury have been described, including end-stage liver disease. However, the CDG diagnostic workflow can be complex as liver disease per se may be associated with abnormal glycosylation. Therefore, we collected serum samples of patients with a wide range of liver pathology to study the performance and yield of two CDG screening methods. Our aim was to identify glycosylation patterns that could help to differentiate between primary and secondary glycosylation defects in liver disease. To this end, we analyzed serum samples of 1042 adult liver disease patients. This cohort consisted of 567 liver transplant candidates and 475 chronic liver disease patients. Our workflow consisted of screening for abnormal glycosylation by transferrin isoelectric focusing (tIEF), followed by in-depth analysis of the abnormal samples with quadruple time-of-flight mass spectrometry (QTOF-MS). Screening with tIEF resulted in identification of 247 (26%) abnormal samples. QTOF-MS analysis of 110 of those did not reveal glycosylation abnormalities comparable with those seen in V-ATPase assembly factor defects. However, two patients presented with isolated sialylation deficiency. Fucosylation was significantly increased in liver transplant candidates compared to healthy controls and patients with chronic liver disease. In conclusion, a significant percentage of patients with liver disease presented with abnormal CDG screening results. However, the glycosylation pattern was not indicative for a V-ATPase assembly factor defect. Advanced glycoanalytical techniques assist in the dissection of secondary and primary glycosylation defects., (© 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Poly(ionic liquid)s are an innovative class of materials with promising properties in gas separation processes that can be used to boost the neat polymer performances. Nevertheless, some of their properties such as stability and mechanical strength have to be improved to render them suitable as materials for industrial applications. This work explored, on the one hand, the possibility to improve gas transport and separation properties of the block copolymer Pebax ® 1657 by blending it with poly[3-ethyl-1-vinyl-imidazolium] diethyl phosphate (PEVI-DEP). On the other hand, Pebax ® 1657 served as a support for the PIL and provided mechanical resistance to the samples. Pebax ® 1657/PEVI-DEP composite membranes containing 20, 40, and 60 wt.% of PEVI-DEP were cast from solutions of the right proportion of the two polymers in a water/ethanol mixture. The PEVI-DEP content affected both the morphology of the dense membranes and gas transport through the membranes. These changes were revealed by scanning electron microscopy (SEM), time-lag, and gravimetric sorption measurements. Pebax ® 1657 and PEVI-DEP showed similar affinity towards CO 2 , and its uptake or solubility was not influenced by the amount of PIL in the membrane. Therefore, the addition of the PIL did not lead to improvements in the separation of CO 2 from other gases. Importantly, PEVI-DEP (40 wt.%) incorporation affected and improved permeability and selectivity by more than 50% especially for the separation of light gases, e.g., H 2 /CH 4 and H 2 /CO 2 , but higher PEVI-DEP concentrations lead to a decline in the transport properties.

R0 resection is paramount in cutaneous squamous cell carcinoma (CSCC) and head and neck squamous cell carcinoma (HNSCC). However, in the setting of recurrence, immunocompromised patients, or non-keratinizing squamous cell carcinoma (SCC) with a spindle growth pattern, tumor borders are difficult, if not impossible, to determine. Fluorescence-guided surgery (FGS) aids in this differentiation. Potential targets for FGS of CSCC and HNSCC were evaluated. Most sections stained intensely for αvβ6 and epidermal growth factor receptor (EGFR) on tumor cells. Normal epithelium stained less for αvβ6 than for EGFR. In addition, soft tissue and stroma stained negative for both, allowing for clear discrimination of the soft tissue margin. Tumor cells weakly expressed urokinase plasminogen activator receptor (uPAR) while expression on stromal cells was moderate. Normal epithelium rarely expressed uPAR, resulting in clear discrimination of superficial margins. Tumors did not consistently express integrin β3, carcinoembryonic antigen, epithelial cell adhesion molecule, or vascular endothelial growth factor A. In conclusion, αvβ6 and EGFR allowed for precise discrimination of SSC at the surgically problematic soft tissue margins. Superficial margins are ideally distinguished with uPAR. In the future, FGS in the surgically challenging setting of cutaneous and mucosal SCC could benefit from a tailor-made approach, with EGFR and αvβ6 as targets.

The last decade has seen an exponential increase in the number of studies focused on novel applications for ionic liquids (ILs). Blends of polymers with ILs have been proposed for use in fuel cells, batteries, gas separation membranes, packaging, etc., each requiring a set of specific physico-chemical properties. In this work, blends of four grades of the poly(ether-ester) multiblock copolymer PolyActive™ with different concentrations of the CO 2 -philic 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide [BMIM][Tf 2 N] were prepared in the form of dense films by a solution casting and solvent evaporation method, in view of their potential use as gas separation membranes for CO 2 capture. Depending on the polymer structure, the material properties could be tailored over a wide range by means of the IL content. All samples were dry-feeling, highly elastic self-standing dense films. The microstructure of the blends was studied by scanning electron microscopy with a backscattering detector, able to observe anisotropy in the sample, while a special topographic analysis mode allowed the visualization of surface roughness. Samples with the longest poly(ethylene oxide terephthalate) (PEOT) blocks were significantly more anisotropic than those with shorter blocks, and this heterogeneity increased with increasing IL content. DSC analysis revealed a significant decrease in the melting enthalpy and melting temperature of the crystalline PEOT domains with increasing IL content, forming an amorphous phase with T g ≈ -50 °C, whereas the polybutylene terephthalate (PBT) phase was hardly affected. This indicates better compatibility of the IL with the polyether phase than the polyester phase. Young's modulus was highest and most IL-dependent for the sample with the highest PEOT content and PEOT block length, due to its high crystallinity. Similarly, the sample with short PEOT blocks and high PBT content also showed a high modulus and tensile strength, but much lower maximum elongation. This study provides a detailed discussion on the correlation between the morphological, thermal, and mechanical properties of these PolyActive™/[BMIM][Tf 2 N] blends.

A detailed comparison of the gas permeability of four Polymers of Intrinsic Microporosity containing Tröger's base (TB-PIMs) is reported. In particular, we present the results of a systematic study of the differences between four related polymers, highlighting the importance of the role of methyl groups positioned at the bridgehead of ethanoanthracene (EA) and triptycene (Trip) components. The PIMs show BET surface areas between 845-1028 m 2 g -1 and complete solubility in chloroform, which allowed for the casting of robust films that provided excellent permselectivities for O 2 /N 2 , CO 2 /N 2 , CO 2 /CH 4 and H 2 /CH 4 gas pairs so that some data surpass the 2008 Robeson upper bounds. Their interesting gas transport properties were mostly ascribed to a combination of high permeability and very strong size-selectivity of the polymers. Time lag measurements and determination of the gas diffusion coefficient of all polymers revealed that physical ageing strongly increased the size-selectivity, making them suitable for the preparation of thin film composite membranes.

Background: Pathogenic germline variants in subunits of succinate dehydrogenase ( SDHB , SDHC and SDHD ) are broadly associated with disease subtypes of phaeochromocytoma-paraganglioma (PPGL) syndrome. Our objective was to investigate the role of variant type (ie, missense vs truncating) in determining tumour phenotype., Methods: Three independent datasets comprising 950 PPGL and head and neck paraganglioma (HNPGL) patients were analysed for associations of variant type with tumour type and age-related tumour risk. All patients were carriers of pathogenic germline variants in the SDHB , SDHC or SDHD genes., Results: Truncating SDH variants were significantly over-represented in clinical cases compared with missense variants, and carriers of SDHD truncating variants had a significantly higher risk for PPGL (p<0.001), an earlier age of diagnosis (p<0.0001) and a greater risk for PPGL/HNPGL comorbidity compared with carriers of missense variants. Carriers of SDHB truncating variants displayed a trend towards increased risk of PPGL, and all three SDH genes showed a trend towards over-representation of missense variants in HNPGL cases. Overall, variant types conferred PPGL risk in the (highest-to-lowest) sequence SDHB truncating, SDHB missense, SDHD truncating and SDHD missense, with the opposite pattern apparent for HNPGL (p<0.001)., Conclusions: SDHD truncating variants represent a distinct group, with a clinical phenotype reminiscent of but not identical to SDHB . We propose that surveillance and counselling of carriers of SDHD should be tailored by variant type. The clinical impact of truncating SDHx variants is distinct from missense variants and suggests that residual SDH protein subunit function determines risk and site of disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)