Effects of Degree and Configuration of Hearing Loss on the Contribution of High- and Low-Frequency Speech Information to Bilateral Speech Understanding

Objectives: The purpose of this study was to examine the effects of degree and configuration of hearing loss on the use of, and benefit from, information in amplified high- and low-frequency speech presented in background noise. Design: Sixty-two adults with a wide range of high- and low-frequency sensorineural hearing loss (5 to 115+ dB HL) participated in the study. To examine the contribution of speech information in different frequency regions, speech understanding in noise was assessed in multiple low- and high-pass filter conditions, as well as a band-pass (713 to 3534 Hz) and wideband (143 to 8976 Hz) condition. To increase audibility over a wide frequency range, speech and noise were amplified based on each individual\u27s hearing loss. A stepwise multiple linear regression approach was used to examine the contribution of several factors to (1) absolute performance in each filter condition and (2) the change in performance with the addition of amplified high- and low-frequency speech components. Results: Results from the regression analysis showed that degree of hearing loss was the strongest predictor of absolute performance for low- and high-pass filtered speech materials. In addition, configuration of hearing loss affected both absolute performance for severely low-pass filtered speech and benefit from extending high-frequency (3534 to 8976 Hz) bandwidth. Specifically, individuals with steeply sloping high-frequency losses made better use of low-pass filtered speech information than individuals with similar low-frequency thresholds but less high-frequency loss. In contrast, given similar high-frequency thresholds, individuals with flat hearing losses received more benefit from extending high-frequency bandwidth than individuals with more sloping losses. Conclusions: Consistent with previous work, benefit from speech information in a given frequency region generally decreases as degree of hearing loss in that frequency region increases. However, given a similar degree of loss, the configuration of hearing loss also affects the ability to use speech information in different frequency regions. Except for individuals with steeply sloping high-frequency losses, providing high-frequency amplification (3534 to 8976 Hz) had either a beneficial effect on, or did not significantly degrade, speech understanding. These findings highlight the importance of extended high-frequency amplification for listeners with a wide range of high-frequency hearing losses, when seeking to maximize intelligibility

Can listening-related fatigue influence well-being? Examining associations between hearing loss, fatigue, activity levels and well-being

ObjectiveWell-being is influenced by the activities we undertake. Hearing loss may reduce well-being directly through increased listening-related fatigue due to cognitive and emotional strain in challenging situations. Hearing loss and hearing device use may also indirectly impact fatigue and well-being by altering the frequency and type of daily-life activities. This review examines the available literature to help understand the relationships.DesignWe provide (i) a summary of the extant literature regarding hearing loss, hearing device use and fatigue in adults, as well as regarding fatigue and daily-life activity (work, social and physical) and (ii) a systematic search and narrative review of the relationships between hearing loss, hearing device use and activity.Study sampleThe systematic search resulted in 66 eligible texts.ResultsData examining well-being in persons with hearing loss are limited. Our literature review suggests that well-being can be related directly and indirectly to hearing loss, hearing device use, activity level and listening-related fatigue.ConclusionsVariations and interactions between hearing loss, hearing device use, fatigue and activity levels can be expected to impact well-being in persons with hearing loss in direct and indirect ways. Future research linking hearing and daily-life fatigue should take account of activity levels

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Moderate Reverberation Does Not Increase Subjective Fatigue, Subjective Listening Effort, or Behavioral Listening Effort in School-Aged Children

Background noise and reverberation levels in typical classrooms have negative effects on speech recognition, but their effects on listening effort and fatigue are less well understood. Based on the Framework for Understanding Effortful Listening, noise and reverberation would be expected to increase both listening effort and fatigue. However, previous investigations of the effects of reverberation for adults have resulted in mixed findings. Some discrepancies in the literature might be accounted for by methodological differences; behavioral and subjective indices of listening effort do not often align in adults. The effects of sustained listening on self-reported fatigue in school-aged children are also not well understood. The purposes of this project were to (1) evaluate the effects of noise and reverberation on listening effort in school-aged children using behavioral and subjective measures, (2) compare subjective and behavioral indices of listening effort, and (3) evaluate the effects of reverberation on self-reported fatigue. Twenty typically developing children (10-17 years old) participated. Participants completed dual-task testing in two rooms that varied in terms of reverberation, an audiometric sound booth and a moderately reverberant room. In each room, testing was completed in quiet and in two levels of background noise. Participants provided subjective ratings of listening effort after completing the dual-task in each listening condition. Subjective ratings of fatigue were completed before and after testing in each level of reverberation. Results revealed background noise, not reverberation, increased behavioral and subjective listening effort. Subjective ratings of perceived performance, ease of listening, and desire to control the listening situation revealed a similar pattern of results as word recognition performance, making them poor candidates for providing an indication of behavioral listening effort. However, ratings of time perception were moderately correlated with behavioral listening effort. Finally, sustained listening for approximately 25 min increased self-reported fatigue, although changes in fatigue were comparable in low and moderately reverberant environments. In total, these data offer no evidence that a moderate level of reverberation increases listening effort or fatigue, but the data do support the reduction of background noise in classrooms