Identification of a series of hair-cell MET channel blockers that protect against aminoglycoside-induced ototoxicity

To identify small molecules that shield mammalian sensory hair cells from the ototoxic side effects of aminoglycoside antibiotics, 10,240 compounds were initially screened in zebrafish larvae, selecting for those that protected lateral-line hair cells against neomycin and gentamicin. When the 64 hits from this screen were retested in mouse cochlear cultures, 8 protected outer hair cells (OHCs) from gentamicin in vitro without causing hair-bundle damage. These 8 hits shared structural features and blocked, to varying degrees, the OHC's mechanoelectrical transducer (MET) channel, a route of aminoglycoside entry into hair cells. Further characterization of one of the strongest MET channel blockers, UoS-7692, revealed it additionally protected against kanamycin and tobramycin and did not abrogate the bactericidal activity of gentamicin. UoS-7692 behaved, like the aminoglycosides, as a permeant blocker of the MET channel; significantly reduced gentamicin-Texas red loading into OHCs; and preserved lateral-line function in neomycin-treated zebrafish. Transtympanic injection of UoS-7692 protected mouse OHCs from furosemide/kanamycin exposure in vivo and partially preserved hearing. The results confirmed the hair-cell MET channel as a viable target for the identification of compounds that protect the cochlea from aminoglycosides and provide a series of hit compounds that will inform the design of future otoprotectants

Viral to metazoan marine plankton nucleotide sequences from the Tara Oceans expedition

A unique collection of oceanic samples was gathered by the Tara Oceans expeditions (2009-2013), targeting plankton organisms ranging from viruses to metazoans, and providing rich environmental context measurements. Thanks to recent advances in the field of genomics, extensive sequencing has been performed for a deep genomic analysis of this huge collection of samples. A strategy based on different approaches, such as metabarcoding, metagenomics, single-cell genomics and metatranscriptomics, has been chosen for analysis of size-fractionated plankton communities. Here, we provide detailed procedures applied for genomic data generation, from nucleic acids extraction to sequence production, and we describe registries of genomics datasets available at the European Nucleotide Archive (ENA, www.ebi.ac.uk/ena). The association of these metadata to the experimental procedures applied for their generation will help the scientific community to access these data and facilitate their analysis. This paper complements other efforts to provide a full description of experiments and open science resources generated from the Tara Oceans project, further extending their value for the study of the world's planktonic ecosystems

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Evaluating a web-based health risk assessment with tailored feedback: what does an expert focus group yield compared to a web-based end-user survey?

Increasingly, Web-based health applications are developed for the prevention and management of chronic diseases. However, their reach and utilization is often disappointing. Qualitative evaluations post-implementation can be used to inform the optimization process and ultimately enhance their adoption. In current practice, such evaluations are mainly performed with end-user surveys. However, a review approach by experts in a focus group may be easier to administer and might provide similar results. The aim of this study was to assess whether industrial design engineers in a focus group would address the same issues as end users in a Web-based survey when evaluating a commercial Web-based health risk assessment (HRA) with tailored feedback. Seven Dutch companies used the HRA as part of their corporate health management strategy. Employees using the HRA (N=2289) and 10 independent industrial designers were invited to participate in the study. The HRA consisted of four components: (1) an electronic health questionnaire, (2) biometric measurements, (3) laboratory evaluation, and (4) individually tailored feedback generated by decision support software. After participating in the HRA as end users, both end users and designers evaluated the program. End users completed an evaluation questionnaire that included a free-text field. Designers participated in a focus group discussion. Constructs from user satisfaction and technology acceptance theories were used to categorize and compare the remarks from both evaluations. We assessed and qualitatively analyzed 294 remarks of 189 end users and 337 remarks of 6 industrial designers, pertaining to 295 issues in total. Of those, 137 issues were addressed in the end-user survey and 148 issues in the designer focus group. Only 7.3% (10/137) of the issues addressed in the survey were also addressed in the focus group. End users made more remarks about the usefulness of the HRA and prior expectations that were not met. Designers made more remarks about how the information was presented to end users, quality of the feedback provided by the HRA, recommendations on the marketing and on how to create more unity in the design of the HRA, and on how to improve the HRA based on these issues. End-user surveys should not be substituted for expert focus groups. Issues identified by end users in the survey and designers in the focus group differed considerably, and the focus group produced a lot of new issues. The issues addressed in the focus group often focused on different aspects of user satisfaction and technology acceptance than those addressed by the survey participants; when they did focus on the same aspects, then the nature of issues differed considerably in conten

Viral to metazoan marine plankton nucleotide sequences from the Tara Oceans expedition

International audienc

Human health risk assessment for aluminium, aluminium oxide, and aluminium hydroxide.

International audienc