Effect of Spectral Channels on Speech Recognition, Comprehension, and Listening Effort in Cochlear-Implant Users

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Kidney failure in mice lacking the tetraspanin CD151

The tetraspanin CD151 is a cell-surface molecule known for its strong lateral interaction with the laminin-binding integrin α3β1. Patients with a nonsense mutation in CD151 display end-stage kidney failure associated with regional skin blistering and sensorineural deafness, and mice lacking the integrin α3 subunit die neonatally because of severe abnormalities in the lung and kidney epithelia. We report the generation of Cd151-null mice that recapitulate the renal pathology of human patients, i.e., with age they develop massive proteinuria caused by focal glomerulosclerosis, disorganization of the glomerular basement membrane, and tubular cystic dilation. However, neither skin integrity nor hearing ability are impaired in the Cd151-null mice. Furthermore, we generated podocyte-specific conditional knockout mice for the integrin α3 subunit that show renal defects similar to those in the Cd151 knockout mice. Our results support the hypothesis that CD151 plays a key role in strengthening α3β1-mediated adhesion in podocytes

Epigenetic prediction of complex traits and mortality in a cohort of individuals with oropharyngeal cancer

Background: DNA methylation (DNAm) variation is an established predictor for several traits. In the context of oropharyngeal cancer (OPC), where 5-year survival is ~ 65%, DNA methylation may act as a prognostic biomarker. We examined the accuracy of DNA methylation biomarkers of 4 complex exposure traits (alcohol consumption, body mass index [BMI], educational attainment and smoking status) in predicting all-cause mortality in people with OPC. Results: DNAm predictors of alcohol consumption, BMI, educational attainment and smoking status were applied to 364 individuals with OPC in the Head and Neck 5000 cohort (HN5000; 19.6% of total OPC cases in the study), followed up for median 3.9 years; inter-quartile range (IQR) 3.3 to 5.2 years (time-to-event—death or censor). The proportion of phenotypic variance explained in each trait was as follows: 16.5% for alcohol consumption, 22.7% for BMI, 0.4% for educational attainment and 51.1% for smoking. We then assessed the relationship between each DNAm predictor and all-cause mortality using Cox proportional-hazard regression analysis. DNAm prediction of smoking was most consistently associated with mortality risk (hazard ratio [HR], 1.38 per standard deviation (SD) increase in smoking DNAm score; 95% confidence interval [CI] 1.04 to 1.83; P 0.025, in a model adjusted for demographic, lifestyle, health and biological variables). Finally, we examined the accuracy of each DNAm predictor of mortality. DNAm predictors explained similar levels of variance in mortality to self-reported phenotypes. Receiver operator characteristic (ROC) curves for the DNAm predictors showed a moderate discrimination of alcohol consumption (area under the curve [AUC] 0.63), BMI (AUC 0.61) and smoking (AUC 0.70) when predicting mortality. The DNAm predictor for education showed poor discrimination (AUC 0.57). Z tests comparing AUCs between self-reported phenotype ROC curves and DNAm score ROC curves did not show evidence for difference between the two (alcohol consumption P 0.41, BMI P 0.62, educational attainment P 0.49, smoking P 0.19). Conclusions: In the context of a clinical cohort of individuals with OPC, DNAm predictors for smoking, alcohol consumption, educational attainment and BMI exhibit similar predictive values for all-cause mortality compared to self-reported data. These findings may have translational utility in prognostic model development, particularly where phenotypic data are not available

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction

Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein–protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Use of an Extra-Tympanic Membrane Electrode to Record Cochlear Microphonics with Click, Tone Burst and Chirp Stimuli

This study determined electrocochleography (ECochG) parameter settings to obtain cochlear microphonics (CM) with less invasive flexible extra-tympanic membrane electrodes. In 24 adult normal-hearing subjects, CMs were elicited by presenting click stimuli at 100 dBnHL, tone bursts (2 kHz) and broadband (BB) CE-chirps® LS (Interacoustics, Middelfart, Denmark), both at 80 dBnHL. Different high-pass filters (HPFs) (3.3 Hz and 100 Hz, respectively) were used to investigate response quality of the CM. CMs were successfully obtained in 92–100% with click-, 75–83% with 2 kHz tone burst- and 58–63% with CE-chirp®-LS stimuli. Click stimuli elicited significantly larger CM amplitudes compared to 2 kHz tone bursts and BB CE-chirp® LS (Interacoustics, Middelfart, Denmark). No significant differences were found between the two different high-pass filter (HPF) settings. The present study shows that it is possible to obtain clear CMs with the flexible extra-tympanic membrane electrodes using click stimuli. In contrast to 2 kHz tone bursts and CE-chirp® (Interacoustics, Middelfart, Denmark) LS, clicks show a significantly higher success rate and are the preferred stimuli to confirm the presence or absence of CMs

P300 in bimodal CI-users

Introduction: Bimodal listeners combine a cochlear implant (CI) with a contralateral hearing aid (HA). Psychoacoustic research shows that bimodal listening can improve speech perception in noise, sound localization, and music appreciation. Nevertheless, a substantial proportion of bimodal listeners cease to wear the HA shortly after implantation. To date, there is no consensus on whether or not bimodal listening is preferred in a given individual or population. This study examines whether endogenous auditory evoked cortical responses can be used to assess bimodal benefit. Methods: Six experienced CI-users were included in the study. Three used a HA in daily life, whereas the others did not wear a HA. All subjects were implanted with either the Nucleus CI24RE(CA) or CI422 and had low-frequency residual hearing in the non-implanted ear. The cognitive P300 response was elicited using an oddball paradigm with a 500 Hz tone-burst as the standard and a 250 Hz tone-burst as the deviant stimulus. P300s were recorded in the CI-only (i.e. with the contralateral ear plugged) and the bimodal condition (i.e. CI and HA or CI and residual hearing, depending on the subject’s daily use). Results: Overall, P300 morphology was clearer in the bimodal compared to the CI-only condition. Amplitudes in the bimodal and CI-only condition were respectively 17.39 μV and 11.63 μV. Latencies were 262 ms (SD 30.0 ms) in the bimodal and 281 ms (SD 49.2 ms) in the CI-only condition. Interestingly, the trend of shorter latencies for the bimodal compared to the CI-only condition was only observed in the subjects who wear a HA in daily life. Conclusion: Preliminary data reveal that the bimodal condition elicited better P300 responses than the CI-only condition, especially in subjects who wear a hearing aid in daily life

The clinical utility of narrow-band chirp auditory brainstem responses : inter-rater reliability and threshold estimation

Background: Tone-burst auditory brainstem responses (TB ABR) have traditionally been used to estimate the configuration of hearing loss in infants. However, more recent studies show that narrow-band (NB) chirps have several advantages over TB ABR. This study compares the reliability of NB-chirp and TB ABR. Methods: ABRs were obtained in 23 adults using TBs and NB chirps with center frequencies at 0.5, 1, 2, and 4 kHz. First, we assessed inter-rater reliability of NB-chirp and TB ABR. Second, we compared signal-to- noise ratios of TB and NB-chirp ABR. Finally, we compared thresholds obtained by pure-tone audiometry, TB ABR, and NB-chirp ABR. Results: Good inter-rater reliability was found for all frequencies. This holds true at maximal as well as threshold level. A preliminary analysis suggests that NB chirps elicits better responses than TBs for all center frequencies except 0.5 kHz, which seems to be difficult to interpret for both TBs and NB chirps. Conclusions: NB chirps can be obtained with good inter-rater reliability. Further statistical analyses and comparisons between behavioral, TB ABR, and NB-chirp ABR thresholds will be presented and discussed