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Objectives: Two pilot studies of AR‐42, a pan‐histone deacetylase inhibitor, in human neurofibromatosis type 2 (NF2), vestibular schwannomas (VS), and meningiomas are presented. Primary endpoints included safety, and intra‐tumoral pharmacokinetics (PK) and pharmacodynamics (PD). Methods: Pilot 1 is a subset analysis of a phase 1 study of AR‐42 in solid tumors, which included NF2 or sporadic meningiomas. Tumor volumes and treatment‐related adverse events (TRAEs) are reported (NCT01129193). Pilot 2 is a phase 0 surgical study of AR‐42 assessing intra‐tumoral PK and PD. AR‐42 was administered for 3 weeks pre‐operatively. Plasma and tumor drug concentrations and p‐AKT expression were measured (NCT02282917). Results: Pilot 1: Five patients with NF2 and two with sporadic meningiomas experienced a similar incidence of TRAEs to the overall phase I trial. The six evaluable patients had 15 tumors (8 VS, 7 meningiomas). On AR‐42, tumor volume increased in six, remained stable in eight, and decreased in one tumor. The annual percent growth rate decreased in eight, remained stable in three, and increased in four tumors. Pilot 2: Four patients with sporadic VS and one patient with meningioma experienced no grade 3/4 toxicities. Expression of p‐AKT decreased in three of four VS. All tumors had higher AR‐42 concentrations than plasma. Conclusions: AR‐42 is safe. Tumor volumes showed a mixed response, but most slowed growth. On a 40‐mg regimen, drug concentrated in tumors and growth pathways were suppressed in most tumors, suggesting this may be a well‐tolerated and effective dose. A phase 2 study of AR‐42 for NF2‐associated tumors appears warranted. Level of Evidence: 1b, 4. [ABSTRACT FROM AUTHOR]

Background: International experience with coronavirus 2019 (COVID‐19) suggests it poses a significant risk of infectious transmission to skull base surgeons, due to high nasal viral titers and the unknown potential for aerosol generation during endonasal instrumentation. The purpose of this study was to simulate aerosolization events over a range of endoscopic procedures to obtain an evidence‐based aerosol risk assessment. Methods: Aerosolization was simulated in a cadaver using fluorescein solution (0.2 mg per 10 mL) and quantified using a blue‐light filter and digital image processing. Outpatient sneezing during endoscopy was simulated using an intranasal atomizer in the presence or absence of intact and modified surgical mask barriers. Surgical aerosolization was simulated during nonpowered instrumentation, suction microdebrider, and high‐speed drilling after nasal fluorescein application. Results: Among the outpatient conditions, a simulated sneeze event generated maximal aerosol distribution at 30 cm, extending to 66 cm. Both an intact surgical mask and a modified VENT mask (which enables endoscopy) eliminated all detectable aerosol spread. Among the surgical conditions, cold instrumentation and microdebrider use did not generate detectable aerosols. Conversely, use of a high‐speed drill produced significant aerosol contamination in all conditions tested. Conclusion: We confirm that aerosolization presents a risk to the endonasal skull base surgeon. In the outpatient setting, use of a barrier significantly reduces aerosol spread. Cold surgical instrumentation and microdebrider use pose significantly less aerosolization risk than a high‐speed drill. Procedures requiring drill use should carry a special designation as an "aerosol‐generating surgery" to convey this unique risk, and this supports the need for protective personal protective equipment. [ABSTRACT FROM AUTHOR]

Abstract: Past observations and numerical modeling find magnetic reconnection to initiate at a localized region and then spread along a current sheet. The rate of spreading has been proposed to be controlled by a number of mechanisms based on the properties within the boundary. At the Earth's magnetopause the spreading speed is also limited by the speed at which a shocked solar wind front can move along the magnetopause boundary. The speed at which a purely north to south rotational discontinuity propagates through the magnetosheath and contacts the magnetopause is measured here using the Block‐Adaptive‐Tree Solar Wind Roe‐Type Upwind Scheme global magnetohydrodynamics model. The propagation speed along the magnetopause is fastest near the nose of the magnetopause and decreases with distance from the subsolar point. The average propagation speed along the dayside magnetopause is 847 km/s. This is significantly larger than observed rates of reconnection spreading at the magnetopause of 30–40 km/s indicating that, for the observed conditions, the speed of front propagation along the magnetopause does not limit or control the spreading rate of reconnection. [ABSTRACT FROM AUTHOR]

The article describes the RadBelt radiation belt model, a new, open-source version of the Dynamic Radiation Environment Assimilation Model (DREAM). It uses the Method of Manufactured Solutions (MMS) to quantitatively verify this open-source version of the DREAM. It investigates the order of convergence for a plethora of code configurations and source teams, and the ability to apply many different diffusion coefficients, including time constant and time varying.

The article focuses on the model verification that secures the proper solution of the equation for code development. The process brings in the radiation belt model called RadBelt as the Dynamic Radiation Environment Assimilation Model (DREAM) that uses the Method of Manufactured Solutions (MMS). It highlights results of the study which include the alternative source function, code performance, and the consideration for source term application.

Integrated lifetime radiation damage may cause spacecraft to become more susceptible to operational anomalies by changing material characteristics of electronic components. This study demonstrates and quantifies the impact of these effects by examining the National Oceanic and Atmospheric Administration (NOAA) National Geophysical Data Center (NGDC) satellite anomaly database. Energetic particle data from the Geostationary Operational Environmental Satellites (GOES) is used to construct the total lifetime particle exposure a satellite has received at the epoch of an anomaly. These values are compared to the satellite's chronological age and the average exposure per year (calculated over two solar cycles.) The results show that many anomalies occur on satellites that have received a total lifetime high-energy particle exposure that is disproportionate to their age. In particular, 10.8% of all events occurred on satellites that received over two times more 20 to 40MeV proton lifetime particle exposure than predicted using an average annual mean. This number inflates to 35.2% for 40 to 80MeV protons and 33.7% for ≥2MeV electrons. Overall, 73.5% of all anomalies occurred on a spacecraft that had experienced greater than two times the expected particle exposure for one of the eight particle populations used in this study. Simplistically, this means that the long term radiation background exposure matters, and that if the background radiation is elevated during the satellite's lifetime, the satellite is likely to experience more anomalies than satellites that have not been exposed to the elevated environment. [ABSTRACT FROM AUTHOR]

Discusses the clinical evaluation and treatment of immune-mediated inner ear disease (IED). Background on IED: Case reports; Diagnosis; Management and treatment.

Examines the shapes of the S1 proximal renal tubule cells to determine if they constructs fractal mathematics. Morphometric measurements made; Analysis of proximal tubule cell; Reference to computer imaging, nephron morphology.

An introduction is presented in which the editor discusses the launch of the open access journal "Laryngoscope Investigative Otolaryngology" and its missions and the acknowledgement of its several authors.

Providing health care to patients with hearing loss during COVID-19 and physical distancing Given that hearing loss currently affects 72.4% of persons over 65[1] and older individuals tend to be hospitalized when affected by COVID-19, it is likely that the global COVID-19 pandemic will impact numerous individuals with hearing loss. The following key points grew from this discussion to ensure optimal communication with people with hearing loss: Be mindful of potential negative impacts of "physical distancing" for people with hearing loss who communicate via spoken language. [Extracted from the article]

A letter to the editor is presented regarding the follow-up of hearing loss in biotinidase deficiency.

Simple Summary: The management of vestibular schwannomas in neurofibromatosis type 2-related schwannomatosis (NF2) is complex. Current treatment strategies include active surveillance, surgery, radiotherapy, and pharmacotherapy. Due to treatment side effects such as hearing loss, balance complaints, or cranial nerve deficits, it remains challenging to find a treatment that achieves a good control of tumor growth with minimal side effects. The present study found that the majority of NF2 patients was treated with proton radiotherapy as salvage treatment for vestibular schwannoma and did not require additional interventions. However, they did experience significant tumor and/or treatment-related side effects. The value of proton radiotherapy as a primary treatment for vestibular schwannomas in NF2 patients remains to be determined. (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. [ABSTRACT FROM AUTHOR]

Highlights: [•] English listeners weight formant more than envelope dynamics in phonetic labeling. [•] Mismatch negativity (MMN) reflects spectrotemporal cue weighting of phonemes. [•] MMN consists of generators reflecting change detection and perceptual organization. [ABSTRACT FROM AUTHOR]

Objectives: We describe a series of otologic complications from impression material used to make hearing aid molds. Methods: We examined a retrospective case series of patients presenting to a tertiary care academic medical center. Results: The presentation, clinical course, and treatment outcomes of 6 patients with complications related to ear molds are discussed. These patients had preexisting abnormalities in their aural anatomy, including tympanic membrane perforations, retraction pockets, and mastoidectomy cavities. Conclusions: Although the majority of patients who have ear canal impressions taken experience no adverse outcomes, hearing aid dispensers should perform a thorough history-taking and physical examination to discern those with abnormal anatomy at risk for complications. These patients may benefit from evaluation in conjunction with an otolaryngologist. [ABSTRACT FROM AUTHOR]

Objective: To describe the presentation and treatment of patients developing pulmonary embolism following translabyrinthine approach for vestibular schwannoma resection. Methods: This was a retrospective case series of patients at 2 academic tertiary medical centers who developed symptomatic pulmonary embolism post-operatively following translabyrinthine approach for vestibular schwannoma resection and were found to have evidence of sigmoid sinus thrombosis. Results: Three patients were identified to have post-operative pulmonary emboli after translabyrinthine approach for vestibular schwannoma resection with sigmoid sinus or internal jugular vein clots in the absence of lower extremity deep vein thrombosis. Caprini scores for these patients were 5 or lower. All patients underwent CT pulmonary angiography and were confirmed to have pulmonary emboli. Two were promptly anticoagulated with heparin drips and transitioned to long-term oral anticoagulation therapy and 1 had delayed anticoagulation. None of these patients suffered from intracranial hemorrhage post-operatively. Conclusions: Patients undergoing translabyrinthine approach for vestibular schwannoma can develop pulmonary embolism from sigmoid sinus entry or thrombosis. No clear guidelines exist for the management of this complication in the setting of recent craniotomy and the risk of intracranial hemorrhage must be considered prior to initiating anticoagulation. [ABSTRACT FROM AUTHOR]

Imbalance and dizziness are disabling symptoms for many patients with vestibular schwannomas (VS) but symptom severity typically does not correlate with the vestibulo-ocular reflex (VOR) amplitude-based metrics used to assess peripheral vestibular damage. In this study, we tested the hypothesis that imbalance and dizziness in patients with VS relate to VOR metrics that are not based on response amplitude. Twenty-four patients with unilateral, sporadic VS tumors were studied, and objective (balance) and subjective (dizziness) vestibular dysfunction was quantified. The VOR was tested using two yaw-axis motion stimuli, low-frequency en-bloc sinusoidal, and high-frequency head-on-body impulsive rotations. Imbalance correlated with VOR precision (the inverse of the trial-to-trial variability) and with low-frequency VOR dynamics (quantified with the time constant), and these two metrics were also strongly correlated. Dizziness correlated with the VOR bias caused by an imbalance in static central vestibular tone, but not with dynamic VOR metrics. VOR accuracy (mean response amplitude relative to the ideal response) was not correlated with the severity of imbalance or dizziness or with measures of VOR precision or time constant. Imbalance in patients with VS, therefore, scales with VOR precision and time constant, both of which appear to reflect the central vestibular signal-to-noise ratio, but not with VOR slow-phase accuracy, which is based on the magnitude of the central vestibular signals. Dizziness was related to the presence of a static central tone imbalance but not to any VOR metrics, suggesting that abnormal perception in VS may be affected by factors that are not captured by yaw-axis VOR measurements. NEW & NOTEWORTHY The severity of symptoms associated with unilateral vestibular schwannomas (VS) is poorly correlated with standard yaw-axis vestibulo-ocular reflex (VOR) metrics that are based on response amplitude. In this study, we show that the balance and perceptual dysfunction experienced by patients with VS scales with VOR metrics that capture information about the central signal-to-noise ratio (balance) and central static tone (dizziness), but are not correlated with the VOR gain, which reflects central signal amplitude. [ABSTRACT FROM AUTHOR]

This case report describes a patient with a facial nerve hemangioma of 8 years' duration that initially caused most of the symptoms of Ménière's syndrome: fullness, sensorineural hearing loss, dizziness, tinnitus, and disruption of balance. The hearing loss was in the high-frequency range (> or = 3,000 Hz); typically, the initial hearing loss in Ménière's syndrome is in the low-frequency range. Mild facial nerve weakness and punctate keratitis due to corneal exposure appeared 8 years later. Contrast-enhanced magnetic resonance imaging and high-resolution computed tomography depicted the lesion and made preoperative diagnosis possible. With meticulous surgical removal of the tumor, which was intertwined with the facial nerve, facial nerve function was preserved. [ABSTRACT FROM AUTHOR]

The author reflects on the criteria and complexities in the assessment and interpretation of review articles to effectively provide clarity and valuable insights into a topic. Topics include the possible requirements by institutions of Institutional Review Board (IRB) approval of review articles, and the types of reviews like systematic reviews, mixed methods reviews, and literature and narrative reviews.

An editorial is presented in which the editor discusses about the types of reviews. They include systematic reviews and meta analysis. The other types of reviews includes mixed methods reviews , scoping, mapping, and systematized reviews and literature and narrative reviews for various types of the papers submitted.

The authors reflect on criteria and complexities of review articles like systematic reviews, meta-analyses and mixed methods reviews. Topics include the non-requirement of Institutional Review Board (IRB) approval for the review of public data and the importance of knowing the article's scholarly purpose, credibility and methodology when conducting reviews.

Objectives: To present the otologic findings of a patient with COVID-19 and complicated acute otitis media, evaluate for the presence of SARS-CoV-2 in middle ear fluid, and assess whether suctioning of middle ear fluid may be aerosol- generating. Methods: The case of a man with SARS-CoV-2 infection and complicated acute otitis media with facial paralysis is presented to illustrate unique clinical decisions made in context of the COVID-19 pandemic. A cadaveric temporal bone was used to simulate droplet spread during suctioning of fluorescein-labelled middle ear fluid and visualized with a blue-light filter. Results: A 23-year-old male who presented with complicated acute otitis media with facial paralysis was found to have an acute infection with SARS-CoV-2, with positive viral PCR of nasopharyngeal swab, and a negative PCR of the middle ear fluid. He was placed on isolation precautions and treated with myringotomy, topical and systemic antibiotics, and antivirals. Consistent with observations during endonasal suctioning, suctioning of middle ear fluid was not found to be aerosol or droplet generating. Conclusion: The case of a patient with active COVID-19 presenting with complicated acute otitis media in whom middle ear fluid was sampled to evaluate the etiology of the infection and the potential middle ear predilection of SARS-CoV-2 is described. This study has implications for the clinical management of patients with both known and unknown SARS-CoV-2 infection who present with ear disease. While middle ear suctioning may not be aerosol-generating, the risk of coughing or prolonged close contact requires heightened precautions during otologic procedures in patients with suspected or confirmed COVID-19. [ABSTRACT FROM AUTHOR]

Purpose: Given clinical activity of AR-42, an oral histone deacetylase inhibitor, in hematologic malignancies and preclinical activity in solid tumors, this phase 1 trial investigated the safety and tolerability of AR-42 in patients with advanced solid tumors, including neurofibromatosis type 2-associated meningiomas and schwannomas (NF2). The primary objective was to define the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Secondary objectives included determining pharmacokinetics and clinical activity. Methods: This phase I trial was an open-label, single-center, dose-escalation study of single-agent AR-42 in primary central nervous system and advanced solid tumors. The study followed a 3 + 3 design with an expansion cohort at the MTD. Results: Seventeen patients were enrolled with NF2 (n = 5), urothelial carcinoma (n = 3), breast cancer (n = 2), non-NF2-related meningioma (n = 2), carcinoma of unknown primary (n = 2), small cell lung cancer (n = 1), Sertoli cell carcinoma (n = 1), and uveal melanoma (n = 1). The recommended phase II dose is 60 mg three times weekly, for 3 weeks of a 28-day cycle. DLTs included grade 3 thrombocytopenia and grade 4 psychosis. The most common treatment-related adverse events were cytopenias, fatigue, and nausea. The best response was stable disease in 53% of patients (95% CI 26.6–78.7). Median progression-free survival (PFS) was 3.6 months (95% CI 1.2–9.1). Among evaluable patients with NF2 or meningioma (n = 5), median PFS was 9.1 months (95% CI 1.9–not reached). Conclusion: Single-agent AR-42 is safe and well tolerated. Further studies may consider AR-42 in a larger cohort of patients with NF2 or in combination with other agents in advanced solid tumors. Trial registration: NCT01129193, registered 5/24/2010. [ABSTRACT FROM AUTHOR]

Although melanoma accounts for approximately 1% of all malignancies, melanoma metastases to the cerebellopontine angles (CPAs) are exceedingly rare. Here we describe a patient with melanoma metastases to the internal auditory canals and CPAs who presented with a remote history of cutaneous melanoma. This patient had a rapidly progressive hearing loss, vestibulopathy, and facial nerve dysfunction. Magnetic resonance imaging demonstrated bilateral, enhancing CPA lesions but was otherwise nonspecific. The diagnosis required a careful history, unilateral surgical resection for tissue acquisition, and histopathologic confirmation. A search for primary cutaneous melanoma at the time of presentation was negative. However, the history of cutaneous melanoma 8 years earlier distinguishes this patient's metastatic disease from solitary primary intracranial melanoma, an equally rare disease. Treatment consists of surgical excision, radiation, chemotherapy, and immunotherapy. The prognosis for patients with melanoma metastases is generally poor, but isolated reports of long-term survival have been described. Metastatic disease to the CPAs must be included in the differential diagnosis for any patient presenting with rapid-onset VIIth or VIIIth cranial nerve symptoms. [ABSTRACT FROM AUTHOR]

We present a case study of the H+, He+, and O+ low‐energy "finger" structure observed by the Van Allen Probe A Helium, Oxygen, Proton, and Electron (HOPE) spectrometer on 26 October 2016. This structure, whose characteristic energy is from approximately tens of eV to a few keV, looks like a "finger" that is rich in O+ and He+, faint in H+ on an energy‐time spectrogram. By using the Space Weather Modeling Framework (SWMF) and Weimer05 electric fields, combined with a dipole or more self‐consistent magnetohydrodynamic (MHD) magnetic field, backward tracing of O+ reveals that the structure is formed by ions with a long drift time from the plasma sheet during the magnetic storm main phase to the inner region with trajectories dominated by eastward drift motion, and the formation depends on the convection electric field model. The heavy ion dominance of the feature is explained by charge exchange losses along the long slow drift paths. Plain Language Summary: Since the early 1970s, a common way to display data from satellite missions in the Earth's magnetosphere is the energy spectrogram, where the flux of observed particles is displayed as a function of particles' energy and the observation time. In this format, many different spectral features have been observed in different regions of the magnetosphere and simulations have been used to understand the formation of these features. Often, these simulations use empirical electric models and dipole magnetic field approximation and observed spectral structures are not able to be replicated. This study investigates the formation mechanism of a type of feature named low‐energy "finger" observed by Van Allen Probe A, using the Space Weather Modeling Framework (SWMF), the Weimer05 electric field as a comparison, combined with a dipole or MHD magnetic field. We find that the inner boundary and the enhanced convection electric field, the source population and the charge exchange losses along the drift paths play a very important role for the formation of this "finger" structure. Key Points: A low‐energy "finger" structure deep in the inner magnetosphere is formed by drift of ions from the plasma sheet during storm main phaseSimulations using the SWMF electric field reproduce the structure much better than using the Weimer05 modelThe heavy ion dominance of the feature is explained by the charge exchange losses along the long slow drift paths [ABSTRACT FROM AUTHOR]

Objective: To determine the efficacy of fibroblast growth factor‐2 (FGF‐2) in treating chronic nonhealing tympanic membrane (TM) perforations. Method: Double‐blinded, randomized placebo controlled phase 2 clinical trial for patients with chronic TM perforations of more than 3 months duration with a cross‐over arm. Patients received either FGF‐2 or placebo (sterile water) saturated gelatin sponge in the perforation after rimming the perforation under topical anesthesia. The perforation was then covered with Tisseel fibrin glue. The primary endpoint was complete closure of the TM perforation. Secondary end points included change in hearing and partial TM closure rates. The TM was examined every 3 weeks with otoendoscopy for closure. The treatment was repeated if there was incomplete closure every 3 weeks up to a total of three treatments per arm. Results: Seventy four patients were recruited for the study. Fifty seven met eligibility criteria and fifty four completed the study. Ten of 14 perforations closed completely in the placebo group (71.4%) and 23 of 40 perforations closed completely in the FGF‐2 treatment group (57.5%), P value =.36. Pure tone averages and word recognition scores were not statistically significantly different between study groups post‐treatment. After initial complete closure, re‐perforation occurred in seven FGF‐2 treated patients and two placebo patients making the effective final closure rate 40% for FGF and 57% for placebo, respectively. Conclusion: No statistically significant difference in tympanic membrane perforation closure rate was found between the FGF‐2 and placebo groups. There were no differences in hearing outcomes between the groups. Level of evidence: 1b. [ABSTRACT FROM AUTHOR]

An editorial is presented on understanding the article's methodology, scholarly purpose, and credibility. Topics include involving a comprehensive literature search, rigorous evaluation of the quantity and quality of research evidence, and analysis of the evidence for synthesising an answer to the research question; and making the relevance to healthcare providers, policymakers, and other key stake-holders.

Objective: Otogenic brain abscesses are one of the most significant life‐threatening complications of otologic infections. Given their low prevalence, otogenic brain abscesses require a high index of suspicion for diagnosis. In this systematic review, we aim to provide an analysis of otogenic brain abscesses and describe common clinical signs and symptoms, bacteriology, location, treatment options, morbidity, and mortality. Data Sources: PubMed, Cochrane CENTRAL database, Google Scholar, and Scopus. Methods: A systematic review of literature was performed using the Preferred Reporting Items for Systematic Reviews and Meta‐analyses recommendations. Variables assessed included clinical signs and symptoms, bacteriology, location, treatment, morbidity, and mortality. Results: Twenty‐nine studies met inclusion and exclusion criteria, corresponding to a total of 1307 otogenic abscess cases for review. Fifty‐five percent of abscesses were found in the temporal lobe and 28% in the cerebellum. Most patients (88.3%) had a history of suppurative chronic otitis media. The most common symptoms were headache, altered mental status, papilledema, and meningeal irritation. Fever, nausea, and vomiting affected about 40% of patients. The most commonly cultured bacterial species was Proteus mirabilis. In addition to antibiotics, most otogenic brain abscesses were treated by burr hole aspiration. Average mortality following advent of computed tomography was 8.11%. Conclusion: Although rare, otogenic brain abscesses may occur as a complication of suppurative otitis media and require a high index of suspicion. Appropriate imaging studies and multidisciplinary expertise are crucial in the diagnosis and management. Level of Evidence: 4. [ABSTRACT FROM AUTHOR]

Meningiomas frequently display activation of the PI3K/AKT/mTOR pathway, leading to elevated levels of phospho-eukaryotic translation initiation factor 4E binding proteins, which enhances protein synthesis; however, it is not known whether inhibition of protein translation is an effective treatment option for meningiomas. We found that human meningiomas expressed high levels of the three components of the eukaryotic initiation factor 4F (eIF4F) translation initiation complex, eIF4A, eIF4E, and eIF4G. The expression of eIF4A and eIF4E was important in sustaining the growth of NF2 -deficient benign meningioma Ben-Men-1 cells, as shRNA-mediated knockdown of these proteins strongly reduced cell proliferation. Among a series of 23 natural compounds evaluated, silvestrol, which inhibits eIF4A, was identified as being the most growth inhibitory in both primary meningioma and Ben-Men-1 cells. Silvestrol treatment of meningioma cells prominently induced G 2 /M arrest. Consistently, silvestrol significantly decreased the amounts of cyclins D1, E1, A, and B, PCNA, and Aurora A. In addition, total and phosphorylated AKT, ERK, and FAK, which have been shown to be important drivers for meningioma cell proliferation, were markedly lower in silvestrol-treated Ben-Men-1 cells. Our findings suggest that inhibiting protein translation could be a potential treatment for meningiomas. [ABSTRACT FROM AUTHOR]

Objectives: We describe a novel use of cortical auditory evoked potentials in the preoperative workup to determine ear candidacy for cochlear implantation. Methods: A 71-year-old male was evaluated who had a long-deafened right ear, had never worn a hearing aid in that ear, and relied heavily on use of a left-sided hearing aid. Electroencephalographic testing was performed using free field auditory stimulation of each ear independently with pure tones at 1000 and 2000 Hz at approximately 10 dB above pure-tone thresholds for each frequency and for each ear. Results: Mature cortical potentials were identified through auditory stimulation of the long-deafened ear. The patient underwent successful implantation of that ear. He experienced progressively improving aided pure-tone thresholds and binaural speech recognition benefit (AzBio score of 74%). Conclusions: Findings suggest that use of cortical auditory evoked potentials may serve a preoperative role in ear selection prior to cochlear implantation. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 2 (NF2) is caused by mutations in the NF2 gene that encodes a tumor-suppressor protein called merlin. NF2 is characterized by formation of multiple schwannomas, meningiomas and ependymomas. Merlin loss-of-function is associated with increased activity of Rac and p21-activated kinases (PAKs) and deregulation of cytoskeletal organization. LIM domain kinases (LIMK1 and 2) are substrate for Cdc42/Rac-PAK and modulate actin dynamics by phosphorylating cofilin at serine-3. This modification inactivates the actin severing and depolymerizing activity of cofilin. LIMKs also translocate into the nucleus and regulate cell cycle progression. Significantly, LIMKs are overexpressed in several tumor types, including skin, breast, lung, liver and prostate. Here we report that mouse Schwann cells (MSCs) in which merlin function is lost as a result of Nf2 exon2 deletion (Nf2ΔEx2) exhibited increased levels of LIMK1, LIMK2 and active phospho-Thr508/505-LIMK1/2, as well as phospho-Ser3-cofilin, compared with wild-type normal MSCs. Similarly, levels of LIMK1 and 2 total protein and active phosphorylated forms were elevated in human vestibular schwannomas compared with normal human Schwann cells (SCs). Reintroduction of wild-type NF2 into Nf2ΔEx2 MSC reduced LIMK1 and LIMK2 levels. We show that pharmacological inhibition of LIMK with BMS-5 decreased the viability of Nf2ΔEx2 MSCs in a dose-dependent manner, but did not affect viability of control MSCs. Similarly, LIMK knockdown decreased viability of Nf2ΔEx2 MSCs. The decreased viability of Nf2ΔEx2 MSCs was not due to caspase-dependent or -independent apoptosis, but rather due to inhibition of cell cycle progression as evidenced by accumulation of cells in G2/M phase. Inhibition of LIMKs arrests cells in early mitosis by decreasing aurora A activation. Our results suggest that LIMKs are potential drug targets for NF2 and tumors associated with merlin deficiency. [ABSTRACT FROM AUTHOR]

Purpose: Several acoustic cues specify any single phonemic contrast. Nonetheless, adult, native speakers of a language share weighting strategies, showing preferential attention to some properties over others. Cochlear implant (CI) signal processing disrupts the salience of some cues: In general, amplitude structure remains readily available, but spectral structure less so. This study asked how well speech recognition is supported if CI users shift attention to salient cues not weighted strongly by native speakers. Method: Twenty adults with CIs participated. The /bα/-/wα/ contrast was used because spectral and amplitude structure varies in correlated fashion for this contrast. Adults with normal hearing weight the spectral cue strongly but the amplitude cue negligibly. Three measurements were made: labeling decisions, spectral and amplitude discrimination, and word recognition. Results: Outcomes varied across listeners: Some weighted the spectral cue strongly, some weighted the amplitude cue, and some weighted neither. Spectral discrimination predicted spectral weighting. Spectral weighting explained the most variance in word recognition. Age of onset of hearing loss predicted spectral weighting but not unique variance in word recognition. Conclusion: The weighting strategies of listeners with normal hearing likely support speech recognition best, so efforts in implant design, fitting, and training should focus on developing those strategies. [ABSTRACT FROM AUTHOR]

Purpose: Several acoustic cues specify any single phonemic contrast. Nonetheless, adult, native speakers of a language share weighting strategies, showing preferential attention to some properties over others. Cochlear implant (CI) signal processing disrupts the salience of some cues: In general, amplitude structure remains readily available, but spectral structure less so. This study asked how well speech recognition is supported if CI users shift attention to salient cues not weighted strongly by native speakers. Method: Twenty adults with CIs participated. The /bα/-/wα/ contrast was used because spectral and amplitude structure varies in correlated fashion for this contrast. Adults with normal hearing weight the spectral cue strongly but the amplitude cue negligibly. Three measurements were made: labeling decisions, spectral and amplitude discrimination, and word recognition. Results: Outcomes varied across listeners: Some weighted the spectral cue strongly, some weighted the amplitude cue, and some weighted neither. Spectral discrimination predicted spectral weighting. Spectral weighting explained the most variance in word recognition. Age of onset of hearing loss predicted spectral weighting but not unique variance in word recognition. Conclusion: The weighting strategies of listeners with normal hearing likely support speech recognition best, so efforts in implant design, fitting, and training should focus on developing those strategies. [ABSTRACT FROM AUTHOR]

Meningiomas constitute about 34% of primary intracranial tumors and are associated with increased mortality in patients with neurofibromatosis type 2 (NF2). To evaluate potential medical therapies for these tumors, we have established a quantifiable orthotopic model for -deficient meningiomas. We showed that telomerase- NF2 immortalized Ben-Men-1 benign meningioma cells harbored a single nucleotide deletion in exon 7 and did NF2 not express the protein, merlin. We also showed that AR-42, a pan-histone deacetylase inhibitor, inhibited NF2 proliferation of both Ben-Men-1 and normal meningeal cells by increasing expression of p16INK4A, p21CIP1/WAF1, and p27KIP1. In addition, AR-42 increased proapoptotic Bimexpression and decreased anti-apoptotic BclXL levels. However, AR-42 predominantly arrested Ben-Men-1 cells at G2-M whereas it induced cell-cycle arrest at G1 in meningeal cells. Consistently, AR-42 substantially decreased the levels of cyclin D1, E, and A, and proliferating cell nuclear antigen in meningeal cells while significantly reducing the expression of cyclin B, important for progression through G2, in Ben-Men-1 cells. In addition, AR-42 decreased Aurora A and B expression. To compare the efficacies of AR-42 and AR-12, a PDK1 inhibitor, we generated and used luciferase-expressing in vivo Ben-Men-1-LucB cells to establish intracranial xenografts that grew over time. While AR-12 treatment moderately slowed tumor growth, AR-42 caused regression of Ben-Men-1-LucB tumors. Importantly, AR-42--treated tumors showed minimal regrowth when xenograft-bearing mice were switched to normal diet. Together, these results suggest that AR-42 is a potential therapy for meningiomas. The differential effect of AR-42 on cell-cycle progression of normal meningeal and meningioma cells may have implications for why AR-42 is well-tolerated while it potently inhibits tumor growth. [ABSTRACT FROM AUTHOR]

Magnetohydrodynamic (MHD) models of the global magnetosphere are very good research tools for investigating the topology and dynamics of the near-Earth space environment. While these models have obvious limitations in regions that are not well described by the MHD equations, they can typically be used (or are used) to investigate the majority of magnetosphere. Often, a secondary consideration is overlooked by researchers when utilizing global models - the effects of solving the MHD equations on a grid, instead of analytically. Any discretization unavoidably introduces numerical artifacts that affect the solution to various degrees. This paper investigates some of the consequences of the numerical schemes and grids that are used to solve the MHD equations in the global magnetosphere. Specifically, the University of Michigan's MHD code is used to investigate the role of grid resolution, numerical schemes, limiters, inner magnetospheric density boundary conditions, and the artificial lowering of the speed of light on the strength of the ionospheric cross polar cap potential and the build up of the ring current in the inner magnetosphere. It is concluded that even with a very good solver and the highest affordable grid resolution, the inner magnetosphere is not grid converged. Artificially reducing the speed of light reduces the numerical diffusion that helps to achieve better agreement with data. It is further concluded that many numerical effects work nonlinearly to complicate the interpretation of the physics within the magnetosphere, and so simulation results should be scrutinized very carefully before a physical interpretation of the results is made. Our conclusions are not limited to the Michigan MHD code, but apply to all MHD models due to the limitations of computational resources. [ABSTRACT FROM AUTHOR]

Abstract: Background: Vestibular schwannomas (VS) frequently express high levels of activated AKT. Small-molecule inhibitors of AKT signalling may have therapeutic potential in suppressing the growth of benign VS and malignant schwannomas. Method: Primary VS and Schwann cells, human malignant schwannoma HMS-97 cells and mouse Nf2–/– Schwann cells and schwannoma cells were prepared to investigate the growth inhibitory and anti-tumour activities of OSU-03012, a celecoxib-derived small-molecule inhibitor of phosphoinositide-dependent kinase-1. Cell proliferation assays, apoptosis, Western blot, in vivo xenograft analysis using SCID mice and immunohistochemistry were performed. Results: OSU-03012 inhibited cell proliferation more effectively in both VS and HMS-97 cells than in normal human Schwann cells. The IC50 of OSU-03012 at 48h was approximately 3.1μM for VS cells and 2.6μM for HMS-97 cells, compared with the IC50 of greater than 12μM for human Schwann cells. Similarly, mouse Nf2–/– schwannoma and Nf2–/– Schwann cells were more sensitive to growth inhibition by OSU-03012 than wild-type mouse Schwann cells and mouse schwannoma cells established from transgenic mice carrying the NF2 promoter-driven SV40 T-antigen gene. Like VS cells, malignant schwannoma HMS-97 cells expressed high levels of activated AKT. OSU-03012 induced apoptosis in both VS and HMS-97 cells and caused a marked reduction of AKT phosphorylation at both the Ser-308 and Thr-473 sites in a dose-dependent manner. In vivo xenograft analysis showed that OSU-03012 was well tolerated and inhibited the growth of HMS-97 schwannoma xenografts by 55% after 9weeks of oral treatment. The anti-tumour activity correlated with reduced AKT phosphorylation. Conclusion: OSU-03012 is a potential chemotherapeutic agent for VS and malignant schwannomas. [Copyright &y& Elsevier]

Abstract: Otosclerosis is a complex disease that results in a common form of conductive hearing loss due to impaired mobility of the stapes. Stapedial motion becomes compromised secondary to invasion of otosclerotic foci into the stapedio-vestibular joint. Although environmental factors and genetic causes have been implicated in this process, the pathogenesis of otosclerosis remains poorly understood. To identify molecular contributors to otosclerosis we completed a microarray study of otosclerotic stapedial footplates. Stapes footplate samples from otosclerosis and control patients were used in the analysis. One-hundred-and-ten genes were found to be differentially expressed in otosclerosis samples. Ontological analysis of differentially expressed genes in otosclerosis provides evidence for the involvement of a number of pathways in the disease process that include interleukin signaling, inflammation and signal transduction, suggesting that aberrant regulation of these pathways leads to abnormal bone remodeling. Functional analyses of genes from this study will enhance our understanding of the pathogenesis of this disease. [Copyright &y& Elsevier]

Objectives: We describe the clinical presentation, imaging, and pathology results of a patient with chondromyxoid fibroma (CMF) involving the mastoid portion of the temporal bone. The literature covering CMF of the head and neck is reviewed. Methods: The patient chart, including imaging and pathology results, was analyzed. An English-language literature review of skull base CMF was performed. Results: Eighty-seven cases of CMF involving the head and neck have been reported in the scientific literature. Sixty-two cases involved the skull base, temporal bone, nasal cavity, or paranasal sinuses. Including this patient, only 8 cases of CMF isolated to the temporal bone have been reported. Most patients experience insidious onset of symptoms such as hearing loss or headache. A computed tomographic scan best shows the relationship of the tumor to surrounding bone and may show intratumoral calcification. Surgical removal was the treatment most commonly used. Although irradiation has been used in selected cases, it is usually avoided because of the potential risk for malignant transformation. Conclusions: Chondromyxoid fibroma, a slow-growing bone tumor, is exceedingly rare within the mastoid, Its differential diagnosis includes chordoma, chondroid chordoma, and low-grade myxoid chondrosarcoma. Surgical excision is the treatment of choice. [ABSTRACT FROM AUTHOR]

Extramedullary plasmacytoma involving the skull base is rare. We describe what we believe is the first reported case of recurrent multiple myeloma presenting as an isolated lesion in the central skull base in a patient with no evidence of systemic involvement. We discuss the patient's presentation, clinical course, and treatment, and we review the relevant scientific literature. [ABSTRACT FROM AUTHOR]

Northern blot analysis has shown that the human neurofibromatosis type 2 (NF2) cDNA hybridizes to multiple RNA species. To examine whether these hybridizing RNA species represent NF2 transcripts, we cloned the complete NF2 cDNA by a combination of techniques: 5′ and 3′ rapid amplification of cDNA ends, RT–PCR, and searching and sequencing the NF2-related cDNA clones from the IMAGE consortium. We showed that human NF2 transcripts initiate at multiple positions. Analogous to those reported previously, NF2 transcripts undergo alternative splicing in the coding exons. We isolated eight alternatively spliced NF2 cDNA isoforms, including one that contains a new exon termed exon 2′, which potentially could encode proteins of different sizes. We assembled the overlapping cDNA fragments, and the longest NF2 cDNA, containing all 17 exons, consists of 6067 nucleotides, which is consistent with the size of the major RNA species hybridized to the NF2 probe. The cDNA has a 425-nucleotide 5′ untranslated region upstream from the ATG start codon, and a long 3′ untranslated region of 3869 nucleotides. We also isolated two shorter NF2 cDNAs that were terminated by different polyadenylation signal sequences, which indicates that differential usage of multiple polyadenylation sites also contributes to the complexity of human NF2 transcripts. By reference to the transcription initiation site mapped, we analyzed the 5′ flanking sequence of the human NF2 gene. Transient transfection analysis in human 293 kidney, SK-N-AS neuroblastoma, and NT2/D1 teratocarcinoma cells with NF2 promoter-luciferase chimeric constructs revealed a core promoter region extending 400 base pairs from the major transcription initiation site. Although multiple regions are required for full promoter activity, a site-directed mutagenesis experiment identified a GC-rich sequence (position −58 to −46), which could be bound by transcription factor Sp1, as a positive cis-acting regulatory element. Cotransfection studies in Drosophila melanogaster SL2 cells showed that Sp1 could activate the NF2 promoter through the GC-rich sequence. [Copyright &y& Elsevier]

An editorial is presented on how to to evaluate a predatory journal. Topics mentioned include the invitations from new open access journals that are not legitimate, the lack of editorial review process and fake science papers that are computer generated, and the guidelines in evaluating the journal.

The article presents guidelines on determining legitimate journals in open-access publishing, noting that predatory journals lack editorial review process.

The article discussess the role played by the open access journals in medical publication; along with peer reviewed papers and scientific information offered by the journal, and list of editors of the journal such as Edward W. Fisher, Robert T. Sataloff and Sandra Schwartz.

The article discusses the increasing number of journals that appear to distribute legitimate scientific data but act in a predatory fashion as of 2018. Topics covered include guidelines for distinguishing legitimate journals, the qualities that mark a predatory journal, and the latter's clearly financial motivation. Also noted are factors to look out for when evaluating whether a journal is predatory.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. [ABSTRACT FROM AUTHOR]