Clinical implications of chloroquine and hydroxychloroquine ototoxicity for COVID-19 treatment: A mini-review

At this time of the COVID-19 pandemic, potentially effective treatments are currently under urgent investigation. Benefits of chloroquine and hydroxychloroquine for the treatment of COVID-19 infection have been proposed and clinical trials are underway. Chloroquine and hydroxychloroquine, typically used for the treatment of malaria and autoimmune diseases, have been considered for off-label use in several countries. In the literature, there are reports of ototoxic effects of the drugs causing damage to the inner ear structures, which then result in hearing loss, tinnitus, and/or imbalance. This mini-review represents a summary of the findings from a systematic search regarding ototoxicity of chloroquine and hydroxychloroquine in the published literature. The characteristics of sensorineural hearing loss and/or tinnitus after chloroquine or hydroxychloroquine treatment can be temporary but reports of persistent auditory and vestibular dysfunction exist. These are not frequent, but the impact can be substantial. Additionally, abnormal cochleovestibular development in the newborn was also reported after chloroquine treatment in pregnant women. The suggested dose of chloroquine for COVID-19 infection is considerably higher than the usual dosage for malaria treatment; therefore, it is plausible that the ototoxic effects will be greater. There are potential implications from this review for survivors of COVID-19 treated with chloroquine or hydroxychloroquine. Patient reports of hearing loss, tinnitus, or imbalance should be noted. Those with troublesome hearing loss, tinnitus and/or imbalance are encouraged to be referred for hearing evaluation and interventions once they are stable. Clinical trials of chloroquine or hydroxychloroquine should also consider including audiological monitoring in the protocol

Aural fullness and transtympanic ventilation tubes in Ménière's disease: a scoping review

Background: Ménière’s Disease (MD) often presents with aural fullness, for reasons that are currently not well understood. Insertion of transtympanic ventilation tubes (VTs) has been historically used for the management of this symptom, though the nature and mechanism of effectiveness is unclear. Objectives: To give an overview of the data available on the effects of VT insertion on aural fullness in MD. Methods: The databases PubMed, EMBASE, Medline, SCOPUS, Web of Science, CENTRAL and Google Scholar were searched to identify relevant records. Records were subsequently analysed and data extracted. Results: Only two studies directly measured the effect of VT insertion on aural fullness, while three others measured it as a placebo to another treatment. Considerable heterogeneity was found among the studies, including conflicting conclusions. Conclusions: There is a paucity of evidence investigating the effect of grommet insertion on aural fullness in MD. This work directs future research into this topic

Audiovestibular clinician experiences and opinions about cisplatin vestibulotoxicity

PurposeVestibulotoxicity associated with cisplatin chemotherapy is known to exist, but the extent, severity, and impact is unclear from the literature. This study explored knowledge, experiences, and opinions of audiovestibular professionals about cisplatin vestibulotoxicity.MethodsAn online survey was disseminated to clinicians working in the audiovestibular field.ResultsNinety-three respondents participated in the survey. Most professionals were aware of potential vestibulotoxicity associated with cisplatin chemotherapy. Thirty-three percent of the respondents reported that they had seen patients with cisplatin vestibulotoxicity. Forty percent of them were confident in making the diagnosis and in managing the patient in this situation. The prevalence and impact of vestibulotoxicity including practicality of the assessment should be considered when designing an effective vestibulotoxicity screening protocol.ConclusionThis study provides a better understanding of cisplatin vestibulotoxicity from the perspectives of audiovestibular clinicians, which will underpin appropriate detection and management of the condition

Intraoperative Monitoring of the Cochlear Nerve during Neurofibromatosis Type-2 Vestibular Schwannoma Surgery and Description of a "Test Intracochlear Electrode".

Objectives  A decision on whether to insert a cochlear implant can be made in neurofibromatosis 2 (NF2) if there is objective evidence of cochlear nerve (CN) function post vestibular schwannoma (VS) excision. We aimed to develop intraoperative CN monitoring to help in this decision. Design  We describe the intraoperative monitoring of a patient with NF2 and our stimulating and recording set up. A novel test electrode is used to stimulate the CN electrically. Setting  This study was set at a tertiary referral center for skull base pathology. Main outcome measure  Preserved auditory brainstem responses leading to cochlear implantation. Results  Electrical auditory brainstem response (EABR) waveforms will be displayed from different stages of the operation. A cochlear implant was inserted at the same sitting based on the EABR. Conclusion  Electrically evoked CN monitoring can provide objective evidence of CN function after VS excision and aid in the decision-making process of hearing rehabilitation in patients who will be rendered deaf

Targeting of Fumarate Hydratase from Mycobacterium tuberculosis Using Allosteric Inhibitors with a Dimeric-Binding Mode.

With the growing worldwide prevalence of antibiotic-resistant strains of tuberculosis (TB), new targets are urgently required for the development of treatments with novel modes of action. Fumarate hydratase (fumarase), a vulnerable component of the citric acid cycle in Mycobacterium tuberculosis (Mtb), is a metabolic target that could satisfy this unmet demand. A key challenge in the targeting of Mtb fumarase is its similarity to the human homolog, which shares an identical active site. A potential solution to this selectivity problem was previously found in a high-throughput screening hit that binds in a nonconserved allosteric site. In this work, a structure-activity relationship study was carried out with the determination of further structural biology on the lead series, affording derivatives with sub-micromolar inhibition. Further, the screening of this series against Mtb in vitro identified compounds with potent minimum inhibitory concentrations

Vestibulotoxicity Associated With Platinum-Based Chemotherapy in Survivors of Cancer: A Scoping Review

Background: Cochleotoxicity following the treatment with platinum-based chemotherapy is well documented. The potential for vestibulotoxicity is still unclear. This scoping review examined the extent of current research literature, summarized research findings and identified research gaps regarding vestibular-related adverse effects associated with platinum-based chemotherapy in survivors of cancer.Methods: Inclusion criteria followed the PICO principles: Participants, adult, and pediatric cancer patients of any cancer type; Intervention, platinum-based chemotherapy (such as cisplatin, carboplatin, and oxaliplatin); Control, none or any; Outcomes, vestibular-related adverse effects. English language articles published since 1978 were retrieved. Seventy-five eligible studies were identified from a systematic literature search, and relevant data were charted, collated, and summarized.Results: Testing for vestibulotoxicity predominately featured functional evaluation of the horizontal semicircular canal using the caloric and rotational tests. The rate of abnormal vestibular function test results after chemotherapy administration varied from 0 to 50%. The results of objective testing did not always correspond to patient symptoms. There is tentative support for patients with pre-existing loss of vestibular function to be more likely to experience vestibular toxicity after dosing with cisplatin.Conclusions: A number of studies reported significant evidence of vestibular toxicities associated with platinum-based chemotherapy, especially cisplatin. This scoping review emphasizes that vestibular toxicity needs more attention and comprehensive evaluation. Specifically, studies that analyse cumulative dose of platinum-based chemotherapy, affected sites of lesion in vestibular end organs, and the correlation and temporal patterns of cochlear and vestibular toxicity are needed

Growth Patterns of Residual Tumor in Preoperatively Growing Vestibular Schwannomas

Objectives To analyze growth of residual vestibular schwannoma (VS) following incomplete tumor resection and determine the influence of residual location and size. Design Retrospective case note and scan review. Setting Tertiary skull base unit. Participants Patients with residual tumor following primary surgery for medium and large unilateral growing vestibular schwanomas between 2006 and 2009. Main Outcome Measures Location of residual VS and post-operative growth, comparing those with more (&gt;5%) or less than 5% of tumor residual (&lt;5%). Results Fifty-two patients had visible residual tumor left behind at surgery. Twenty had &lt; 5% and 32 had &gt; 5% residual. The residual growth rates were 38% overall, 20% in &lt; 5%, and 50% in &gt; 5% residuals. There was no significant difference in growth rates at different residual locations. Median follow-up was 6.4 years. Conclusions There is a greater risk of regrowth of residuals &gt; 5%. All positions of residual tumor can regrow, and the preoperative tumor size plays a role in this. Further data is needed to confirm if residual tumor in the fundus is less likely to grow.</jats:p

Challenges of future multimedia QoE monitoring for internet service providers

The ever-increasing network traffic and user expectations at reduced cost make the delivery of high Quality of Experience (QoE) for multimedia services more vital than ever in the eyes of Internet Service Providers (ISPs). Real-time quality monitoring, with a focus on the user, has become essential as the first step in cost-effective provisioning of high quality services. With the recent changes in the perception of user privacy, the rising level of application-layer encryption and the introduction and deployment of virtualized networks, QoE monitoring solutions need to be adapted to the fast changing Internet landscape. In this contribution, we provide an overview of state-of-the-art quality monitoring models and probing technologies, and highlight the major challenges ISPs have to face when they want to ensure high service quality for their customers

LHC Magnet Tests: Operational Techniques and Empowerment for Successful Completion

The LHC magnet tests operation team developed various innovative techniques, particularly since early 2004, to complete the superconductor magnet tests by Feb. 2007. Overall and cryogenic priority handling, rapid on-bench thermal cycling, rule-based goodness evaluation on round-the-clock basis, multiple, mashed web systems are some of these techniques applied with rigour for successful tests completion in time. This paper highlights these operation empowerment tools which had a pivotal role for success. A priority handling method was put in place to enable maximum throughput from twelve test benches, having many different constraints. For the cryogenics infrastructure, it implied judicious allocation of limited resources to the benches. Rapid On-Bench Thermal Cycle was a key strategy to accelerate magnets tests throughput, saving time and simplifying logistics. First level magnet appraisal was developed for 24 hr decision making so as to prepare a magnet further for LHC or keep it on standby. Web based systems (Tests Management and E-Traveller) were other essential ideas to track & coordinate various stages of tests handled by different teams

Infection with 2009 H1N1 influenza virus primes for immunological memory in human nose-associated lymphoid tissue, offering cross-reactive immunity to H1N1 and avian H5N1 viruses

Influenza is a highly contagious mucosal infection in the respiratory tract. 2009 pandemic H1N1 (pH1N1) virus infection resulted in substantial morbidity and mortality in humans. Little is known on whether immunological memory develops following pH1N1 infection and whether it provides protection against other virus subtypes. Enzyme-linked immunosorbent spot assay was used to analyze hemagglutinin (HA)-specific memory B cell responses after virus antigen stimulation in nasal-associated lymphoid tissues (NALT) from children and adults. Individuals with serological evidence of previous exposure to pH1N1 showed significant cross-reactive HA-specific memory B responses to pH1N1, seasonal H1N1(sH1N1) and avian H5N1(aH5N1) viruses upon pH1N1 virus stimulation. pH1N1 virus antigen elicited stronger cross-reactive memory B cell responses than sH1N1 virus. Intriguingly, aH5N1 virus also activated cross-reactive memory responses to sH1N1 and pH1N1 HAs in those who had previous pH1N1 exposure, and that correlated well with the memory response stimulated by pH1N1 virus antigen. These memory B cell responses resulted in cross-reactive neutralizing antibodies against sH1N1, 1918 H1N1 and aH5N1viruses. 2009 pH1N1 infection appeared to have primed human host with B cell memory in NALT that offers cross-protective mucosal immunity against not only H1N1 but also aH5N1 viruses. These findings may have important implications to future vaccination strategies against influenza. It will be important to induce and/or enhance such cross-protective mucosal memory B cells