Clinical translation of anti-inflammatory effects of Prevotella histicola in Th1, Th2, and Th17 inflammation.

Introduction: EDP1815 is a non-colonizing pharmaceutical preparation of a single stain of Prevotella histicola isolated from the duodenum of a human donor. We report here preclinical and clinical studies showing that the action of EDP1815, an orally delivered and gut restricted single strain of commensal bacteria can regulate inflammatory responses throughout the body. Methods: Supported by evidence for anti-inflammatory activity in three preclinical mouse models of Th1-, TH2-, and Th17-mediated inflammation, EDP1815 was tested clinically in three Phase 1b studies in patients with psoriasis, patients with atopic dermatitis, and healthy volunteers in a KLH skin challenge model. Results: Preclinically, EDP1815 was efficacious in all three mouse models of inflammation, showing reduction in skin inflammation as well as related tissue cytokines. In the Phase 1b studies, EDP1815 was found to be well tolerated by participants, with a safety profile comparable to placebo, including no severe or consistent side-effects reported, and no evidence of immunosuppression with no opportunistic infection occurring in these studies. In psoriasis patients, signs of clinical efficacy were seen after 4 weeks of treatment, which continued beyond the treatment period in the higher-dose cohort. In atopic dermatitis patients, improvements were seen throughout the key physician-and patient-reported outcomes. In a healthy-volunteer study of a KLH-induced skin inflammatory response, consistent anti-inflammatory effects were seen in two cohorts through imaging-based measures of skin inflammation. Discussion: This is the first report demonstrating clinical effects from targeting peripheral inflammation with a non-colonizing gut-restricted single strain of commensal bacteria, providing proof of concept for a new class of medicines. These clinical effects occur without systemic exposure of EDP1815 or modification of the resident gut microbiota, and with placebo-like safety and tolerability. The breadth of these clinical effects of EDP1815, combined with its excellent safety and tolerability profile and oral administration, suggests the potential for a new type of effective, safe, oral, and accessible anti-inflammatory medicine to treat the wide range of diseases driven by inflammation.Clinical Trial Registration: EudraCT # 2018-002807-32; EudraCT # 2018-002807-32; NL8676; https://clinicaltrials.gov/ct2/show/NCT03733353; http://www.trialregister.nl.

Reference equivalent threshold sound pressure levels for the Wireless Automated Hearing Test System.

This paper presents reference equivalent threshold sound pressure levels (RETSPLs) for the Wireless Automated Hearing Test System (WAHTS), a recently commercialized device developed for use as a boothless audiometer. Two initial studies were conducted following the ISO 389-9 standard [ISO 389-9 (2009). "Acoustics-Reference zero for the calibration of audiometric equipment. Part 9: Preferred test conditions for the determinations of reference hearing threshold levels" (International Organization for Standardization, Geneva)]. Although the standard recruitment criteria are intended to yield otologically normal test subjects, the recruited populations appeared to have slightly elevated thresholds [5-10 dB hearing level (HL)]. Comparison of WAHTS thresholds to other clinical audiometric equipment revealed bias errors that were consistent with the elevated thresholds of the RETSPL populations. As the objective of RETSPLs is to ensure consistent thresholds regardless of the equipment, this paper presents the RETSPLs initially obtained following ISO 389-9:2009 and suggested correction to account for the elevated HLs of the originally recruited populations. Two additional independent studies demonstrate the validity of these corrected thresholds.

Real-time infection prediction with wearable physiological monitoring and AI to aid military workforce readiness during COVID-19.

Infectious threats, like the COVID-19 pandemic, hinder maintenance of a productive and healthy workforce. If subtle physiological changes precede overt illness, then proactive isolation and testing can reduce labor force impacts. This study hypothesized that an early infection warning service based on wearable physiological monitoring and predictive models created with machine learning could be developed and deployed. We developed a prototype tool, first deployed June 23, 2020, that delivered continuously updated scores of infection risk for SARS-CoV-2 through April 8, 2021. Data were acquired from 9381 United States Department of Defense (US DoD) personnel wearing Garmin and Oura devices, totaling 599,174 user-days of service and 201 million hours of data. There were 491 COVID-19 positive cases. A predictive algorithm identified infection before diagnostic testing with an AUC of 0.82. Barriers to implementation included adequate data capture (at least 48% data was needed) and delays in data transmission. We observe increased risk scores as early as 6 days prior to diagnostic testing (2.3 days average). This study showed feasibility of a real-time risk prediction score to minimize workforce impacts of infection.

Alterations in auditory brain stem response distinguish occasional and constant tinnitus.

BACKGROUNDThe heterogeneity of tinnitus is thought to underlie the lack of objective diagnostic measures.METHODSLongitudinal data from 20,349 participants of the Swedish Longitudinal Occupational Survey of Health (SLOSH) cohort from 2008 to 2018 were used to understand the dynamics of transition between occasional and constant tinnitus. The second part of the study included electrophysiological data from 405 participants of the Swedish Tinnitus Outreach Project (STOP) cohort.RESULTSWe determined that with increasing frequency of the occasional perception of self-reported tinnitus, the odds of reporting constant tinnitus after 2 years increases from 5.62 (95% CI, 4.83-6.55) for previous tinnitus (sometimes) to 29.74 (4.82-6.55) for previous tinnitus (often). When previous tinnitus was reported to be constant, the odds of reporting it as constant after 2 years rose to 603.02 (524.74-692.98), suggesting that once transitioned to constant tinnitus, the likelihood of tinnitus to persist was much greater. Auditory brain stem responses (ABRs) from subjects reporting nontinnitus (controls), occasional tinnitus, and constant tinnitus show that wave V latency increased in constant tinnitus when compared with occasional tinnitus or nontinnitus. The ABR from occasional tinnitus was indistinguishable from that of the nontinnitus controls.CONCLUSIONSOur results support the hypothesis that the transition from occasional to constant tinnitus is accompanied by neuronal changes in the midbrain leading to a persisting tinnitus, which is then less likely to remit.FUNDINGThis study was supported by the GENDER-Net Co-Plus Fund (GNP-182), the European Union's Horizon 2020 grants no. 848261 (Unification of Treatments and Interventions for Tinnitus [UNITI]) and no. 722046 (European School for Interdisciplinary Tinnitus Research [ESIT]).

Sex-Dependent Aggregation of Tinnitus in Swedish Families.

Twin and adoption studies point towards a genetic contribution to tinnitus; however, how the genetic risk applies to different forms of tinnitus is poorly understood. Here, we perform a familial aggregation study and determine the relative recurrence risk for tinnitus in siblings (λs). Four different Swedish studies (N = 186,598) were used to estimate the prevalence of self-reported bilateral, unilateral, constant, and severe tinnitus in the general population and we defined whether these 4 different forms of tinnitus segregate in families from the Swedish Tinnitus Outreach Project (STOP, N = 2305). We implemented a percentile bootstrap approach to provide accurate estimates and confidence intervals for λs. We reveal a significant λs for all types of tinnitus, the highest found being 7.27 (95% CI (5.56-9.07)) for severe tinnitus, with a higher susceptibility in women (10.25; 95% CI (7.14-13.61)) than in men (5.03; 95% CI (3.22-7.01)), suggesting that severity may be the most genetically influenced trait in tinnitus in a sex-dependent manner. Our findings strongly support the notion that genetic factors impact on the development of tinnitus, more so for severe tinnitus. These findings highlight the importance of considering tinnitus severity and sex in the design of large genetic studies to optimize diagnostic approaches and ultimately improve therapeutic interventions.

Relationship between headaches and tinnitus in a Swedish study.

The heterogeneity of tinnitus is likely accounting for the lack of effective treatment approaches. Headaches have been related to tinnitus, yet little is known on how headaches impact tinnitus. We use cross-sectional data from the Swedish Tinnitus Outreach Project to i) evaluate the association between headaches and tinnitus (n = 1,984 cases and 1,661 controls) and ii) investigate the phenotypic characteristics of tinnitus subjects with tinnitus (n = 660) or without (n = 1,879) headaches. In a multivariable logistic regression model, headache was significantly associated with any tinnitus (odds ratio, OR = 2.61) and more so with tinnitus as a big problem (as measured by the tinnitus functional index, TFI ≥ 48; OR = 5.63) or severe tinnitus (using the tinnitus handicap inventory, THI ≥ 58; OR = 4.99). When focusing on subjects with tinnitus, the prevalence of headaches was 26% and reached 40% in subjects with severe tinnitus. A large number of socioeconomic, phenotypic and psychological characteristics differed between headache and non-headache subjects with any tinnitus. With increasing tinnitus severity, fewer differences were found, the major ones being vertigo, neck pain and other pain syndromes, as well as stress and anxiety. Our study suggests that headaches could contribute to tinnitus distress and potentially its severity.

Impact of Temporomandibular Joint Complaints on Tinnitus-Related Distress.

There is increasing evidence of associations between the presence of temporomandibular joint (TMJ) disorders and tinnitus. It has been recently proposed that tinnitus patients with TMJ complaints could constitute a subtype, meaning a subgroup of tinnitus patients responsive to specific treatments. Tinnitus patients with TMJ complaints are often young women with somatosensory features of their tinnitus. Here, we investigate the socio-economic factors, phenotypic characteristics and psychological variables of tinnitus subjects from the Swedish Tinnitus Outreach Project, with (n = 486) or without (n = 1,996) TMJ complaints. The prevalence of TMJ complaints was greater in tinnitus subjects with severe tinnitus (36%) when compared to those with any tinnitus (19%), strongly indicating the contribution of TMJ problems to the severity of tinnitus. Comparing subgroups with or without TMJ complaints in the whole sample, differences were found regarding a large number of socioeconomic, phenotypic, and psychological characteristics. Subjects with TMJ complaints were more often women, more often reported stress as the cause of tinnitus, were more severely affected by tinnitus, scored worse in measures of psychological well-being and life quality, and were more often affected by problems tolerating sounds, headache, vertigo/dizziness, and neck pain. In addition, they more often reported pulsating and tonal tinnitus, somatic modulation of tinnitus, and aggravation of tinnitus by loud sounds and stress. When focusing the analysis in subjects with tinnitus as a big problem using the Tinnitus Functional Index cut-off ≥ 48, or with severe tinnitus according to the Tinnitus Handicap Inventory cut-off ≥ 58, the impact of somatosensory modulations and stress on tinnitus were greater in subjects with TMJ complaints in comparison to those without. In light of these results, we hypothesize that stress could contribute to the co-occurrence of TMJ problems and tinnitus and also to the development of severe tinnitus. Our study supports the need of involving dental care and stress management in the holistic treatment of patients with severe tinnitus.

Influence of talker discontinuity on cortical dynamics of auditory spatial attention.

In everyday acoustic scenes, listeners face the challenge of selectively attending to a sound source and maintaining attention on that source long enough to extract meaning. This task is made more daunting by frequent perceptual discontinuities in the acoustic scene: talkers move in space and conversations switch from one speaker to another in a background of many other sources. The inherent dynamics of such switches directly impact our ability to sustain attention. Here we asked how discontinuity in talker voice affects the ability to focus auditory attention to sounds from a particular location as well as neural correlates of underlying processes. During electroencephalography recordings, listeners attended to a stream of spoken syllables from one direction while ignoring distracting syllables from a different talker from the opposite hemifield. On some trials, the talker switched locations in the middle of the streams, creating a discontinuity. This switch disrupted attentional modulation of cortical responses; specifically, event-related potentials evoked by syllables in the to-be-attended direction were suppressed and power in alpha oscillations (8-12 Hz) were reduced following the discontinuity. Importantly, at an individual level, the ability to maintain attention to a target stream and report its content, despite the discontinuity, correlates with the magnitude of the disruption of these cortical responses. These results have implications for understanding cortical mechanisms supporting attention. The changes in the cortical responses may serve as a predictor of how well individuals can communicate in complex acoustic scenes and may help in the development of assistive devices and interventions to aid clinical populations.

Auditory brainstem response latency in forward masking, a marker of sensory deficits in listeners with normal hearing thresholds.

In rodent models, acoustic exposure too modest to elevate hearing thresholds can nonetheless cause auditory nerve fiber deafferentation, interfering with the coding of supra-threshold sound. Low-spontaneous rate nerve fibers, important for encoding acoustic information at supra-threshold levels and in noise, are more susceptible to degeneration than high-spontaneous rate fibers. The change in auditory brainstem response (ABR) wave-V latency with noise level has been shown to be associated with auditory nerve deafferentation. Here, we measured ABR in a forward masking paradigm and evaluated wave-V latency changes with increasing masker-to-probe intervals. In the same listeners, behavioral forward masking detection thresholds were measured. We hypothesized that 1) auditory nerve fiber deafferentation increases forward masking thresholds and increases wave-V latency and 2) a preferential loss of low-spontaneous rate fibers results in a faster recovery of wave-V latency as the slow contribution of these fibers is reduced. Results showed that in young audiometrically normal listeners, a larger change in wave-V latency with increasing masker-to-probe interval was related to a greater effect of a preceding masker behaviorally. Further, the amount of wave-V latency change with masker-to-probe interval was positively correlated with the rate of change in forward masking detection thresholds. Although we cannot rule out central contributions, these findings are consistent with the hypothesis that auditory nerve fiber deafferentation occurs in humans and may predict how well individuals can hear in noisy environments.

Auditory Brainstem Response Latency in Noise as a Marker of Cochlear Synaptopathy.

Evidence from animal and human studies suggests that moderate acoustic exposure, causing only transient threshold elevation, can nonetheless cause "hidden hearing loss" that interferes with coding of suprathreshold sound. Such noise exposure destroys synaptic connections between cochlear hair cells and auditory nerve fibers; however, there is no clinical test of this synaptopathy in humans. In animals, synaptopathy reduces the amplitude of auditory brainstem response (ABR) wave-I. Unfortunately, ABR wave-I is difficult to measure in humans, limiting its clinical use. Here, using analogous measurements in humans and mice, we show that the effect of masking noise on the latency of the more robust ABR wave-V mirrors changes in ABR wave-I amplitude. Furthermore, in our human cohort, the effect of noise on wave-V latency predicts perceptual temporal sensitivity. Our results suggest that measures of the effects of noise on ABR wave-V latency can be used to diagnose cochlear synaptopathy in humans. SIGNIFICANCE STATEMENT: Although there are suspicions that cochlear synaptopathy affects humans with normal hearing thresholds, no one has yet reported a clinical measure that is a reliable marker of such loss. By combining human and animal data, we demonstrate that the latency of auditory brainstem response wave-V in noise reflects auditory nerve loss. This is the first study of human listeners with normal hearing thresholds that links individual differences observed in behavior and auditory brainstem response timing to cochlear synaptopathy. These results can guide development of a clinical test to reveal this previously unknown form of noise-induced hearing loss in humans.

Functional modeling of the human auditory brainstem response to broadband stimulation.

Population responses such as the auditory brainstem response (ABR) are commonly used for hearing screening, but the relationship between single-unit physiology and scalp-recorded population responses are not well understood. Computational models that integrate physiologically realistic models of single-unit auditory-nerve (AN), cochlear nucleus (CN) and inferior colliculus (IC) cells with models of broadband peripheral excitation can be used to simulate ABRs and thereby link detailed knowledge of animal physiology to human applications. Existing functional ABR models fail to capture the empirically observed 1.2-2 ms ABR wave-V latency-vs-intensity decrease that is thought to arise from level-dependent changes in cochlear excitation and firing synchrony across different tonotopic sections. This paper proposes an approach where level-dependent cochlear excitation patterns, which reflect human cochlear filter tuning parameters, drive AN fibers to yield realistic level-dependent properties of the ABR wave-V. The number of free model parameters is minimal, producing a model in which various sources of hearing-impairment can easily be simulated on an individualized and frequency-dependent basis. The model fits latency-vs-intensity functions observed in human ABRs and otoacoustic emissions while maintaining rate-level and threshold characteristics of single-unit AN fibers. The simulations help to reveal which tonotopic regions dominate ABR waveform peaks at different stimulus intensities.

Individual differences reveal correlates of hidden hearing deficits.

Clinical audiometry has long focused on determining the detection thresholds for pure tones, which depend on intact cochlear mechanics and hair cell function. Yet many listeners with normal hearing thresholds complain of communication difficulties, and the causes for such problems are not well understood. Here, we explore whether normal-hearing listeners exhibit such suprathreshold deficits, affecting the fidelity with which subcortical areas encode the temporal structure of clearly audible sound. Using an array of measures, we evaluated a cohort of young adults with thresholds in the normal range to assess both cochlear mechanical function and temporal coding of suprathreshold sounds. Listeners differed widely in both electrophysiological and behavioral measures of temporal coding fidelity. These measures correlated significantly with each other. Conversely, these differences were unrelated to the modest variation in otoacoustic emissions, cochlear tuning, or the residual differences in hearing threshold present in our cohort. Electroencephalography revealed that listeners with poor subcortical encoding had poor cortical sensitivity to changes in interaural time differences, which are critical for localizing sound sources and analyzing complex scenes. These listeners also performed poorly when asked to direct selective attention to one of two competing speech streams, a task that mimics the challenges of many everyday listening environments. Together with previous animal and computational models, our results suggest that hidden hearing deficits, likely originating at the level of the cochlear nerve, are part of "normal hearing."

Spectrotemporal modulation sensitivity for hearing-impaired listeners: dependence on carrier center frequency and the relationship to speech intelligibility.

Poor speech understanding in noise by hearing-impaired (HI) listeners is only partly explained by elevated audiometric thresholds. Suprathreshold-processing impairments such as reduced temporal or spectral resolution or temporal fine-structure (TFS) processing ability might also contribute. Although speech contains dynamic combinations of temporal and spectral modulation and TFS content, these capabilities are often treated separately. Modulation-depth detection thresholds for spectrotemporal modulation (STM) applied to octave-band noise were measured for normal-hearing and HI listeners as a function of temporal modulation rate (4-32 Hz), spectral ripple density [0.5-4 cycles/octave (c/o)] and carrier center frequency (500-4000 Hz). STM sensitivity was worse than normal for HI listeners only for a low-frequency carrier (1000 Hz) at low temporal modulation rates (4-12 Hz) and a spectral ripple density of 2 c/o, and for a high-frequency carrier (4000 Hz) at a high spectral ripple density (4 c/o). STM sensitivity for the 4-Hz, 4-c/o condition for a 4000-Hz carrier and for the 4-Hz, 2-c/o condition for a 1000-Hz carrier were correlated with speech-recognition performance in noise after partialling out the audiogram-based speech-intelligibility index. Poor speech-reception and STM-detection performance for HI listeners may be related to a combination of reduced frequency selectivity and a TFS-processing deficit limiting the ability to track spectral-peak movements.

Spectrotemporal modulation sensitivity as a predictor of speech intelligibility for hearing-impaired listeners.

BACKGROUND: A model that can accurately predict speech intelligibility for a given hearing-impaired (HI) listener would be an important tool for hearing-aid fitting or hearing-aid algorithm development. Existing speech-intelligibility models do not incorporate variability in suprathreshold deficits that are not well predicted by classical audiometric measures. One possible approach to the incorporation of such deficits is to base intelligibility predictions on sensitivity to simultaneously spectrally and temporally modulated signals. PURPOSE: The likelihood of success of this approach was evaluated by comparing estimates of spectrotemporal modulation (STM) sensitivity to speech intelligibility and to psychoacoustic estimates of frequency selectivity and temporal fine-structure (TFS) sensitivity across a group of HI listeners. RESEARCH DESIGN: The minimum modulation depth required to detect STM applied to an 86 dB SPL four-octave noise carrier was measured for combinations of temporal modulation rate (4, 12, or 32 Hz) and spectral modulation density (0.5, 1, 2, or 4 cycles/octave). STM sensitivity estimates for individual HI listeners were compared to estimates of frequency selectivity (measured using the notched-noise method at 500, 1000, 2000, and 4000 Hz), TFS processing ability (2 Hz frequency-modulation detection thresholds for 500, 1000, 2000, and 4000 Hz carriers) and sentence intelligibility in noise (at a 0 dB signal-to-noise ratio) that were measured for the same listeners in a separate study. STUDY SAMPLE: Eight normal-hearing (NH) listeners and 12 listeners with a diagnosis of bilateral sensorineural hearing loss participated. DATA COLLECTION AND ANALYSIS: STM sensitivity was compared between NH and HI listener groups using a repeated-measures analysis of variance. A stepwise regression analysis compared STM sensitivity for individual HI listeners to audiometric thresholds, age, and measures of frequency selectivity and TFS processing ability. A second stepwise regression analysis compared speech intelligibility to STM sensitivity and the audiogram-based Speech Intelligibility Index. RESULTS: STM detection thresholds were elevated for the HI listeners, but only for low rates and high densities. STM sensitivity for individual HI listeners was well predicted by a combination of estimates of frequency selectivity at 4000 Hz and TFS sensitivity at 500 Hz but was unrelated to audiometric thresholds. STM sensitivity accounted for an additional 40% of the variance in speech intelligibility beyond the 40% accounted for by the audibility-based Speech Intelligibility Index. CONCLUSIONS: Impaired STM sensitivity likely results from a combination of a reduced ability to resolve spectral peaks and a reduced ability to use TFS information to follow spectral-peak movements. Combining STM sensitivity estimates with audiometric threshold measures for individual HI listeners provided a more accurate prediction of speech intelligibility than audiometric measures alone. These results suggest a significant likelihood of success for an STM-based model of speech intelligibility for HI listeners.