Rushden, United Kingdom

Immunity After Cochlear Implantation and Perilymph Molecular Profiles in Sensorineural Hearing Loss

With the progress of technologies and surgical methods, cochlear implantation, initially proposed only to patients with completely non-functional inner ear, can be now performed on individuals with still some measurable hearing left in some frequencies. Such patients can additionally benefit from a special treatment by electric-acoustic stimulation (EAS). Combining the electric stimulation with cochlear implant (CI) and acoustic amplification of residual hearing using a conventional hearing aid (HA) can drastically improve one's quality of life and ameliorate the performance in noisy environment as well as music perception. Since the main condition for EAS is the residual hearing preservation, it is important to understand the reasons of its loss post-cochlear implantation. This loss can occur in 2 periods: - Early after surgery (˂ 1 month): mainly due to the trauma from electrode insertion. This risk decreases with the development of surgical techniques. Another possible reason is early inflammation processes in the cochleae. - Later after surgery (˃ 1 month): occurs mainly about 3 months post-implantation in 30-40 % of patients. This loss is the main reason for dropping out the EAS leaving the patient to rely on CI only. Animal studies suggest that the delayed residual hearing loss might happen as consequence of cochlear fibrosis development, supposedly due to the inflammation and foreign body response to the CI materials within the cochlea. In its natural state, the cochlea does not contain any immune cells and is well protected from immune stimulation by infectious agents. Cochlear implantation, however, provides a single clinical cause for infectious or autoimmune fibrosis. Such immune response might be provoked by autoantigens against cochlear proteins like Cochline or TectB. This study aims to search blood markers of immunisation against inner ear proteins after cochlear implantation. Another goal is to seek potential biomarkers of delayed residual hearing loss directly in perilymph. Proteomic analysis will be performed using Liquid Chromatography - High Resolution Mass Spectroscopy (HRMS) technique. The main objective of this study is - to identify, in the perilymph of implanted patients, biomarkers predictive of the delayed residual hearing loss - to identify blood biomarkers predictive of delayed residual hearing loss in implanted patients The secondary objectives are - to describe qualitatively and quantitatively the time evolution for blood biomarkers of interest after cochlear implantation - to correlate quantitative values of identified biomarkers with clinical data of implanted patients - to identify perilymph and blood biomarkers of early residual hearing loss post-cochlear implantation - depending on molecular profiles identified, to study metabolic pathways and mechanisms involved in delayed residual hearing loss post-cochlear implantation - to seek for blood indicators in favour of anti-cochlear immunisation through screening for peripheral blood mononuclear cells (PBMC) - to create a bio collection of human perilymph and blood serum biobank of cochlear implants users for future proteomics/molecular studies

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REVErsing Airway Remodelling With Tezepelumab

Tezepelumab is a human IgG2l monoclonal antibody (mAb) directed against TSLP. Double-blind, randomized controlled trials comparing Tezepelumab treatment against placebo demonstrate net positive benefits in asthma patients. Animal research currently indicates that blocking TSLP can prevent bronchial remodelling in murine models (Chen et al. 2013), but no such observations have been attempted in humans. Within this context, the aim of this protocol is to perform a first randomized controlled trial evaluating how Tezepelumab affects the bronchial morphology (and computed tomographic variables in general) of asthmatic patients. In parallel, the investigators also hope to reproduce clinical benefits and perform a transcriptomic study that will juxtapose changes in genetic expression with changes in bronchial morphology and inflammatory signatures. The general hypothesis is that tezepelumab treatment is capable of at least partially reversing bronchial remodelling as detected on computed-tomographic (CT) scans. The investigators also expect such reversal to occur within a unique physiological repair environment that will be reflected by transcriptomic profiles. The primary objective of this protocol is therefore to compare the change-from-baseline in the average percentage bronchial wall area (%WA = (wall area (mm2)/ (wall area (mm2) + lumen area (mm2)))×100) for patients with asthma and undergoing 6 months of tezepelumab treatment with a similar population treated via placebo. Secondarily, continued treatment effects associated with longer treatment (12 months) or remanence after treatment stopping at 6 months will also be quantified. Study arms will additionally be compared in terms of: - Changes in radiomics (CT-scan data); - Changes in exacerbation rates and lung function; - Changes in serum club cell secretory protein (CCSP); - Changes in nasal single-cell transcriptomic signatures. This study also has an exploratory component designed to characterize the physiological repair environment. In depth radiomic and transcriptomic (including single-cell analyses) profiling will be performed. Finally, the capacity of baseline data to predict the response to tezepelumab will also be explored.

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