Objectives: The objective of the study was to investigate the association between untreated age-related hearing loss and cognitive impairment in Mandarin-speaking older adults living in China.Methods: Older adults  were recruited. All participants completed a pure tone audiometric hearing assessment, Hearing Impairment-Montreal Cognitive Assessment Test (HI-MoCA), and a computerized neuropsychology test battery (CANTAB). The Mandarin version of the De Jong Gierveld Loneliness Scale was used to measure the loneliness, and the Mandarin version of the 21-item Depression Anxiety Stress Scale (DASS-21) was used to measure the current severity of a range of symptoms common to depression, stress, and anxiety of the participants.Results: A multiple stepwise regression analysis showed that the average of four mid-frequency thresholds in the better ear was related to CANTAB Paired Associates Learning , and the global cognitive function score (HI-MoCA) . The average of three high frequencies in the better ear was significantly associated with CANTAB Delayed Matching to Sample , and Spatial Working Memory .Conclusion: The results revealed a significant relationship between age-related hearing loss and cognitive impairment in Mandarin-speaking older adults. These research outcomes have clinical implications specifically for hearing health care professionals in China and other populations that speak a tonal language, especially when providing hearing rehabilitation. An estimated 1.57 billion people worldwide had hearing loss in 2019, accounting for 20.3% of the global population . ApproxiStudies conducted with non-tonal language speakers have established a relationship between untreated age-related hearing loss and cognitive impairment and dementia . Those wApproximately 50% of the population of the world speaks a tonal language, e.g., Mandarin, Cantonese. In tonal languages, changes in pitch (tone) at the monosyllabic level convey lexical meaning of a word. As pitch is the important factor here, tonal language perception can be equated with music perception. This view is supported by evidence that speaking tonal language leads to enhanced pitch perception in music. The benefits of music training and tonal language experience are bidirectional, and a background in either domain improves processing in the other domain . FurtherThere is also psychophysiological evidence that suggests that a tonal language background maybe associated with enhanced general cognitive abilities. A study conducted by using the Corsi blocks tapping test has shown that the Cantonese speakers had a superior working memory related to pitch perception relative to English speakers .Therefore, it is possible to hypothesize that tonal language speakers are likely to have better working memory in their later life compared with non-tonal language older adults. As hearing sensitivity is strongly associated with age, this raises the question whether speaking a tonal language is a protective factor for cognitive decline in older adults.p > 0.05).There are a handful of studies that have investigated the associations between cognitive function and untreated hearing loss in tonal language speakers. However, these studies have reported conflicting findings. An analysis of the cognitive assessments utilized in studies that investigated the association between hearing loss and cognitive impairment/dementia in tonal language speakers have not thoroughly assessed cognition, or often used verbally loaded test materials that rely on audition, i.e., some of the materials are presented orally–aurally. For example, a population-based study of age-related hearing loss and dementia in Taiwan was only able to assess the cognitive status of the participants as impaired or normal by psychiatric diagnosis, not enabling a full quantitative analysis . A cohorThe underlying mechanism between hearing loss and cognitive impairment is yet to be established. However, the posited underlying factors of this mechanism may include low education, hypertension, obesity, smoking, depression, physical inactivity, and low social contact .Therefore, this study explored the potential association between hearing loss and cognitive impairment in Mandarin-speaking older adults in China using a non-verbal cognitive assessment test battery, controlling for a number of potential confounders.Participants were recruited through social media advertisements, flyers, and community centers in Beijing. Ethics approval for this study was obtained from The University of Western Australia—Human Research Ethics Committee (RA/4/20/5538) and Beijing Tongren Hospital, Capital Medical University (TRECKY2019-090). All procedures were carried out in accordance with these approvals, and the participants all provided written informed consent.Inclusion criteria: Native Mandarin speakers, aged 60 years and above with hearing impairment were invited to participate in the study. Exclusion criteria: Those not in general state of good health or unable to perform tasks required in the cognition evaluation session due to an underlying physical or mental condition, or those who had previously worn or currently wearing hearing aids or a hearing implant were excluded from the study. Those who could not complete the Motor Screening Task (MOT) module of the Cambridge Neuropsychological Test Battery (CANTAB)  due to iThe assessment methods comprised measurements of hearing ability, cognition function, loneliness, and mental health status.After enrollment, all participants completed a baseline questionnaire capturing demographic information, and data on alcohol consumption , smoking , self-reported chronic disease history , leisure activities, as well as marital status and living arrangements. Leisure activities were classified into recreational, intellectual, physical, and social categories . Living Pure-tone audiometry (PTA) was assessed with an audiometer  and supra-aural earphone (TDH-39). For all participants, bilateral air-conduction thresholds were measured at 0.25, 0.5, 1, 2, 4, 6, and 8 kHz; and bone-conduction thresholds were measured at 0.5, 1, 2, and 4 kHz, through standard audiometric assessment conducted by a qualified audiologist in a soundproof booth at the audiology center of the Beijing Institute of Otolaryngology.Evaluation of hearing loss was deployed by two different methods: the traditional four frequency average of hearing thresholds at 0.5, 1, 2, and 4 kHz, and the three high frequency average of hearing thresholds at 4, 6, and 8 kHz in the better ear, noted, respectively, as 4FA and 3HFA. These were analyzed as continuous variables. For the purpose of summarizing the hearing loss of the study cohort, the 4FA hearing loss was classified using the World Health Organization (WHO) grades of hearing impairment , respectThe global cognitive functions of the subjects were tested using the Montreal Cognitive Assessment Test (MoCA) for the hearing impaired. A Mandarin version of the MoCA (version 7.2) was adapted , which wFor the visuospatial and executive tasks, an answer sheet was given to the subject to be completed as instructed. For all other tasks, the subjects were asked to verbally answer or respond. For example, for the memory recall section, a series of words were presented at a rate of 2 s per word , comparable to the standard verbal administration of the original MoCA. In the attention tasks, for both the forward and backward order digits repetition, all the numbers were presented at a rate of 1.5 s . For the digits series task, requiring the participant to identify the digit 1 among a string of digits from 0 to 9 by tapping the table, the HI-MoCA visually presented a series of numbers at a rate of 1.5 s between numbers for the subject to observe and respond to by tapping the table. In the language task, both sentences are presented for 9 s.All the HI-MoCA tests were administered by an audiologist, who received formal training from a senior neurology physician with advanced clinical experience and completed the certificated training course via the MoCA website.Non-verbal cognition was assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB) . The CANEvaluation of cognitive function for this study was focused on working and episode memory, processing speed, and spatial information processing. Therefore, the relevant test items were chosen from the CANTAB test battery, including delayed matching to sample (DMS), paired associates learning (PAL), and spatial working memory (SWM), respectively. Assessment commenced with a test of motor function, to qualify the participant for further assessment.The motor screening task provides a general assessment of whether vision, sensorimotor deficits, or lack of comprehension, which, if present, would limit the collection of valid data from the participant . It invoThe DMS test assesses both simultaneous visual matching ability and short-term visual recognition memory, for non-verbalizable patterns . DMS is The PAL test assesses episodic visuospatial memory, learning, and association ability . This teThe SWM test requires retention and manipulation of visuospatial information. This self-ordered test has obvious executive function demands and provides a measure of non-verbal working memory, visuospatial working memory, and strategy use . SWM is The Mandarin version of the six-item De Jong Gierveld Loneliness Scale was used to measure the loneliness of the subjects . In thisThe Depression Anxiety Stress Scales (DASS-21) is a questionnaire to assess the symptoms of depression, anxiety, and stress . The 21 All statistical analyses were performed using SPSS version 25 . A multiple forward stepwise regression analysis was used to examine the relationship between cognitive functions and other variables, including age, gender, smoking and alcohol consumption, chronic medical history, education years, loneliness and mental health, and PTA thresholds of better ear average across 500 Hz–8 kHz. The different CANTAB modules and HI-MoCA scores were entered as dependent variables, respectively. The collinearity tests were examined during each stepwise regression analysis.p-values, and the Akaike Information Criterion (AIC) was used to set a limit on the total number of variables included in the final model. The criteria of entry of each variable was a probability of F ≤ 0.05 and removal of each variable a probability of F ≥ 0.10.At each step of the regression analysis, variables were added based on The demographic information, cognitive function scores, and other descriptive data of this study population are presented in For descriptive purposes, the better ear 4FA was used to group the participants; 65 had normal hearing, 106 had mild hearing loss, 54 had moderate hearing loss, 34 had moderately severe hearing loss, 31 had severe hearing loss, and three had profound hearing loss, as shown in p < 0.001), PAL error for 6 shapes (p < 0.05), and that the better ear 3HFA significantly predicted SWM within error (p < 0.05) and DMS correct percent (p < 0.05). The detailed results are shown in The multiple stepwise regression analyses revealed that the better ear 4FA significantly predicted HI-MoCA scores  and multiple domains of non-verbal cognitive abilities in Mandarin-speaking older adults. To the best of our knowledge, this is the first study to elucidate the association between hearing loss and cognitive function by using the hearing impairment version MoCA and a non-verbal neurocognitive assessment tool with tonal language participants.Our results are consistent with previous cross-sectional studies of pure-tone audiometric hearing loss and cognitive decline and impairment in non-tonal language speakers . Our resp = 0.004) and PAL error (six shapes) . This finding suggests that self-reported hearing loss may be a useful indicator when evaluating the relationship between hearing loss and cognitive impairment. This finding accords with another study, which showed that self-reported hearing loss was significantly associated with both baseline and follow-up cognitive impairment  and PAL . Prior studies have noted that episodic memory impairments are one of the earliest signs of amnestic mild cognitive impairment, Alzheimer’s disease, and other dementias .Short-term visual memory function in this study was assessed using DMS module of the CANTAB test battery. Linear regression showed that while high-frequency hearing in the better ear was significantly associated with the DMS score, mid-frequency hearing was not associated with the DMS score. This finding is consistent with previous research  on non-tVisual memory and learning ability were measured by PAL task of CANTAB test battery. There was a significant positive correlation between mid-frequency hearing in (4FA) in the better ear, and PAL error (six shapes). Previous studies have also demonstrated that performance on the PAL task is highly associated with cognition impairment, and can differentiate subjects with Alzheimer’s disease from normal controls with high sensitivity and specificity . HoweverTwo types of leisure activities  were observed in the regression model to be associated with PAL error , but not PAL error (6 shapes). Prior studies that have noted the importance of participation in leisure activities, which has been associated with the reduced risk of cognitive impairment after controlling for age, gender, and education . In thisSpatial working memory requires retention and manipulation of visuospatial information. The SWM task has notable demands on executive function and provides a measure of strategy as well as working memory. This study showed that high frequency hearing is significantly associated with SWM within error, but not with mid-frequency hearing. This result may be explained, as noted earlier, by the fact that high frequencies show a decrease in sensitivity at least a decade earlier than for the mid-frequency speech frequencies . HoweverEducation was significantly associated with almost all the cognitive-dependent variables, including HI-MoCA and CANTAB DMS, PAL, and SWM. These results corroborate the findings of a great deal of the previous work in this field. Lower rates of late-life dementia are associated with higher education levels during earlier life . Early eAnother important finding was that social loneliness and overall loneliness  were significantly associated with both SWM between error and SWM strategy. Several reports have shown that both loneliness and social isolation are associated with cognitive decline . The litBetween 20 and 40% of the elderly in Western countries are reported to be lonely , and theThis study contributes evidence to the growing global body of evidence that hearing loss and cognitive decline are significantly associated, also in Mandarin-speaking older adults. While the risk of hearing loss to cognition has not been determined, the association is something that hearing health professionals need to bear in mind when managing and counseling their patients.One of the limitations in this study is that the age of participants recruited generally reflected their level of hearing loss and that there were relatively fewer participants with increasing severity of hearing loss. However, this is consistent with the prevalence of hearing loss in the population in relation to age. This study was designed as a longitudinal study, so as to examine the association between ARHL and cognitive decline over time. Another potential limitation is that participant fatigue may have affected some of the more strenuous tests.These findings warrant longitudinal studies to better understand the association between hearing loss and cognitive impairment over time and also to investigate how confounding factors contribute to the cognitive functions overall. Recent studies have studied the impact of hearing aids and cochlear implantation on cognitive functions of older adults with hearing loss . The resThis study provides more evidence for the association between hearing loss and cognitive impairment in Mandarin-speaking older adults. This study revealed that the hearing loss has a significant relationship with cognitive impairment in a Chinese-speaking population.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the University of Western Australia-Human Research Ethics Committee, the Institutional Review Board of Beijing Tongren Hospital, Capital Medical University. The participants provided their written informed consent to participate in this study.DJ and XF designed the experiments. XF carried out the experiments and wrote the manuscript. XF, BL, SW, RE, and DJ analyzed the experimental results. RE, DJ, BL, and SW reviewed the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The editor KL has declared a shared institutional affiliation with the authors XF, BL, and SW at the time of review.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The occurrence of unilateral sensorineural hearing loss (SNHL) during school age is relatively rare and accounts for approximately 6% of all deafness in childhood. We present two cases involving children who were diagnosed with SNHL associated with Sjögren's syndrome (SS). Case 1: An eight-year-old girl with an approximately two-year clinical history of gradual hearing loss was diagnosed with SNHL associated with SS based on histological findings of inflammation in the salivary glands and the presence of serum anti-Sjögren's syndrome-A antibody. Case 2: An eight-year-old boy with acute idiopathic thrombocytopenic purpura in whom unilateral hearing loss, which was not associated with any problems in daily life, was detected during hospitalization and who was finally diagnosed with SNHL and SS. Steroid treatment was ineffective for both patients. The previously unrecognized combination of SNHL with SS should be considered in the diagnosis of unilateral SNHL, even in children. Congenital sensorineural hearing loss (SNHL) is one of the most common congenital disorders , with a We herein report two cases of children with unilateral SNHL associated with Sjögren's syndrome (SS).Case 1The patient was an eight-year-old girl with hearing loss in her right ear. She passed hearing screening (an AABR examination) at birth. At approximately six years of age, she noticed difficulty in daily communication with others. A pure tone audiometry test showed profound hearing loss in the right ear and normal hearing in the left ear Figure . In an a Case 27 cells . In a bone marrow examination, normal proliferation and differentiation of lymphoid and myeloid lineage cells with increased megakaryocytes were observed, a typical finding of ITP. He suffered from acute gastroenteritis with remarkable thrombocytopenia and was admitted to our hospital for the management and treatment of gastroenteritis and thrombocytopenia. During admission, he noticed hearing difficulty in his left ear. Pure tone audiometry demonstrated profound hearing loss in the left ear from 2,000 to 8,000 Hz  based on isolated thrombocytopenia  with the presence of platelet-associated IgG at 66 ng/10z Figure . Temporaz Figure . His serOn the 12th day, he was treated with intravenous immunoglobulin (1 g/kg) for thrombocytopenia, showing a good response with a platelet count increase from 7,000 to 177,000 within three days. Steroid treatment was started  on the 19th day of admission, and tapered off after 18 days. His platelet level successfully remained at >50,000/μL; however, no remarkable change in hearing activity in his left ear was observed by ABR or DPOAEs in the three months after the treatment.These two children, in whom unilateral hearing loss was noticed at school age, were diagnosed with unilateral SNHL associated with SS. The affected region causing hearing loss was identified as intra-cochlea based on a DPOAE test and pure tone audiometry. Because the condition was not responsive to steroid and immunoglobulin therapy, it was hypothesized that inflammation triggered by an autoimmune reaction causing atrophy and necrosis had irreversibly damaged the cochlea. We unexpectedly found the co-existence of SS in both patients, and it was hypothesized that the autoimmune reaction induced by SS might have, at least in part, played a role in the irreversible damage of the cochlea. The pathophysiological rationale for our speculation is as follows. (i) A recent report demonstrated that SS patients diagnosed in adulthood showed a very high prevalence 95.2%) of SNHL in high-frequency ranges . Both ca.2% of SNThe pathophysiology of the inner ear involvement in SS is still unknown. Calzada and Hatzopoulos have reported vacuolization and thickening of the basement membrane as well as deposits of immune complexes in the stria vascularis, producing arterial microvasculature ischemia of the basal turn of the cochlea, where high frequencies are detected . It is pIn contrast, there have been no reports of hearing loss in pediatric SS, and the hearing loss of patients was not responsive to steroid treatment. Thus, it might be possible that hearing loss and SS were simply coincidental. It is possible that congenital CMV infection may underlie the cause of deafness because the sensitivity of the CMV test is not 100%; furthermore, a trivial congenital malformation in the inner ear might have been undetectable by MRI or CT.The previously unrecognized combination of SNHL with SS should be considered in the diagnosis of unilateral SNHL, even in children. Further study, with a greater number of cases and in vitro studies to help determine the actual reaction cascade, would be needed to conclude that SS can directly cause hearing loss by an immune reaction in the inner ear cells, and to determine whether an early diagnosis and steroid treatment can change the hearing prognosis of patients with SNHL with SS.


A CC hearing aid in the unilateral atretic ear did not significantly improve the speech recognition score in a symmetrical noise presentation condition. The binaural hearing benefits of CC hearing aids in unilateral aural atresia were predominantly considered a diotic summation. Other benefits of binaural hearing remain to be investigated.Severe conductive hearing loss due to unilateral aural atresia leads to auditory and developmental disorders, such as difficulty in hearing in challenging situations. Bone conduction devices compensate for the disability but unfortunately have several disadvantages. The aim of this study was to evaluate the benefits of cartilage conduction (CC) hearing aids for speech perception in unilateral aural atresia. Eleven patients with unilateral aural atresia were included. Each participant used a CC hearing aid in the atretic ear. Speech recognition scores in the binaural hearing condition were obtained at low speech levels to evaluate the contribution of aided atretic ears to speech perception. Speech recognition scores were also obtained with and without presentation of noise. These assessments were compared between the unaided and aided atretic ear conditions. Speech recognition scores at low speech levels were significantly improved under the aided atretic ear condition ( Unilateral hearing deficit deprives individuals of the benefits of binaural hearing naturally present in individuals with normal hearing and disturbs auditory development ,2,3,4. TAir conduction (AC) hearing aids are usually used as an intervention device in most individuals with hearing loss. However, some pathological ear conditions, such as atretic ear, prevent the use of AC hearing aids. Bone conduction (BC) hearing aids are effective in atretic ears and are therefore used instead of AC hearing aids in individuals with aural atresia. Unfortunately, BC hearing aids also have several disadvantages concerning comfort, esthetics, and stability ,6. Its aOn attaching a transducer on the aural cartilage, the patient is able to perceive loud sounds , and thiHearing via CC is not simple, since both direct-AC sound and airborne sound generated by vibrating the cartilaginous portion of the ear canal result in sound perception . CC hearIn clinical use, patients who tried CC hearing aids reported benefits, such as improved conversation in noisy situations and improved sound localization, and they wished to continue using them . Our preAll participants were recruited from a previous clinical trial of CC hearing aids . Eleven The average threshold at 500, 1000, and 2000 Hz in atretic ears aided with a CC hearing aid was 35.6 ± 9.0 dB. When the thresholds in the atretic ear were measured in the sound field, normal ear was masked with narrow band noise. In some participants, adequate masker level could not be determined using a plateau method due to a large difference between the two ears, and the unaided threshold in the atretic ear  could not be obtained. Judging from the aided threshold and functional gain in bilateral atretic ears in the previous study, the functional gains for the participants were estimated to be 30–40 dB [The contribution of CC hearing aids in atretic ears to speech recognition was estimated. The normal ears allowed conversation in quiet environments. The contribution of CC hearing aids in quiet situations is difficult to estimate at more than a moderate speech level. Speech recognition scores were obtained at low speech levels under the unaided and aided conditions, and the scores were compared. In Japan, speech audiometry is conducted using 57-S or 67-S word lists including 50- or 20-monosyllable words, respectively. They are authorized by the Japan Audiological Society . In ordeThe speech recognition scores with and without noise were compared under the unaided and aided conditions. A loudspeaker for speech presentation was located 1 m in front of each participant. Two loudspeakers for noise presentation were individually located at ±45 degrees azimuth at a distance of 1 m according to ISO 8253-3 (2012). The 57-S word lists and speech-weighted noise were employed as the test material and noise, respectively. The power spectrum of the speech-weighted noise was constant from 125 Hz to 1000 Hz, with a roll-off of 12 dB/oct . The preThe above-mentioned assessments were performed in a soundproof room . The calibration of the loudspeakers was carried out with a sound level meter .Speech recognition scores at two speech levels were analyzed using two-way analysis of variance (ANOVA), with hearing aid (aided with CC hearing aid or not) and speech levels as within-subject factors. The impact of noise on speech recognition scores were also analyzed using two-way ANOVA, with hearing aid and noise (with and without noise presentation) as within-subject factors. Statistical ANOVA was performed using SPSS ver. 22 . The Bonferroni method was used as a post-hoc correction of the multiple comparisons test after ANOVA. Significance was set at 0.05.p < 0.01), but not for the hearing aid  = 3.07, p = 0.11). A significant interaction between them was found  = 7.54, p < 0.05). In the post-hoc tests at the dB (Max-10), the speech recognition score under the aided condition was found to be 54.0 ± 20.0%, which was significantly higher than that under the unaided condition, which was 44.7 ± 19.4% (p < 0.05).The obtained speech performance-intensity functions determined the dB (Max) of each participant. The average dB (Max) was 35.4 ± 12.1 dB. p < 0.01), but not for the hearing aid  = 1.56, p = 0.24). No interaction between them was found  = 0.14, p = 0.72). Speech recognition scores significantly decreased with noise presentation. No differences in the decrease were found between the unaided and aided conditions.The speech recognition scores decreased under the noise presentation condition B. ANOVA The benefits of CC hearing aids in unilateral aural atresia were evaluated. We investigated the effects of a CC hearing aid in the atretic ear on speech recognition at low speech levels and in presence of noise. Only the benefit of diotic summation on speech recognition was obtained in this study.Unilateral aural atresia induces severe conductive hearing loss of the atretic ear, which causes a large difference between the two ears. The amplification gain with CC hearing aids is estimated to be 30–40 dB , reducinAnother advantage of binaural hearing is improved hearing in noisy situations. Individuals with binaural hearing can benefit from head shadow effects just by attending to the ear with the better SNR . FurtherMost patients with unilateral aural atresia who have tried CC hearing aids in atretic ears wished to continuously use the aids, as they subjectively perceived the benefits of binaural hearing after daily use . This stThe benefits of binaural hearing with CC hearing aids in unilateral aural atresia were evaluated. By decreasing the left–right difference in hearing, speech recognition scores improved at low speech levels. No improvements in speech recognition in noise were found. The binaural hearing benefits of CC hearing aids in unilateral aural atresia were predominantly considered to be a diotic summation.


It has been noted in the literature that there is a gap between clinical assessment and real-world performance. Real-world conversations entail visual and audio information, yet there are not any audiological assessment tools that include visual information. Virtual reality (VR) technology has been applied to various areas, including audiology. However, the use of VR in speech-in-noise perception has not yet been investigated.The purpose of this study was to investigate the impact of virtual space (VS) on speech performance and its feasibility to be used as a speech test instrument. We hypothesized that individuals’ ability to recognize speech would improve when visual cues were provided.A total of 30 individuals with normal hearing and 25 individuals with hearing loss completed pure-tone audiometry and the Korean version of the Hearing in Noise Test (K-HINT) under three conditions—conventional K-HINT (cK-HINT), VS on PC (VSPC), and VS head-mounted display (VSHMD)—at –10 dB, –5 dB, 0 dB, and +5 dB signal-to-noise ratios (SNRs). Participants listened to target speech and repeated it back to the tester for all conditions. Hearing aid users in the hearing loss group completed testing under unaided and aided conditions. A questionnaire was administered after testing to gather subjective opinions on the headset, the VSHMD condition, and test preference.U test showed statistical significance (P<.05) between the two groups under all test conditions. Hearing aid use led to better integration of audio and visual cues. Statistical significance through the Mann-Whitney U test was observed for –5 dB (P=.04) and 0 dB (P=.02) SNRs under the cK-HINT condition, as well as for –10 dB (P=.007) and 0 dB (P=.04) SNRs under the VSPC condition, between hearing aid and non–hearing aid users. Participants reported positive responses across almost all items on the questionnaire except for the weight of the headset. Participants preferred a test method with visual imagery, but found the headset to be heavy.Provision of visual information had a significant impact on speech performance between the normal hearing and hearing impaired groups. The Mann-Whitney Findings are in line with previous literature that showed that visual cues were beneficial for communication. This is the first study to include hearing aid users with a more naturalistic stimulus and a relatively simple test environment, suggesting the feasibility of VR audiological testing in clinical practice. Hearing loss is a major health concern for the global society due to its negative consequences on individuals’ lives. These consequences include, but are not limited to, communication, employment, cognitive decline, social participation, and quality of life -5. Heariyes or press the button”) when he or she hears the tone, even if the tone is soft. Speech testing is also performed in the sound field with one or more loudspeakers  of the NH group and 52% [13/25] of the HI group) and encouraged hearing aid use (50% [15/30] of the NH group and 44% [11/25] of the HI group). The cK-HINT, which did not provide any visual information, required the greatest amount of listening effort, as reported by the NH  and HI  groups. A total of 97% (29/30) of participants in the NH group and 88% (22/25) of participants in the HI group showed willingness to complete the test if available in clinical practice.Simulation of reality and immersion were the main differences reported by the groups. For this question, individuals were able to select more than one option. A total of 63% (19/30) and 83% (25/30) of participants in the NH group selected immersion and simulation of a real-world environment, respectively, as differences between the conditions. For the HI group, 72% (18/25) and 52% (13/25) of participants selected immersion and reality simulation, respectively, as differences between the conditions. Other responses included “test is interesting,” “being able to concentrate during testing,” and “visual cues  were available.” This adds value to VR’s strengths and participants’ subjective responses regarding test preference and tests that better promote hearing aid use and assess hearing problems.A substantial majority of the participants reported that the cK-HINT would be a better assessment tool for measuring auditory performance because it did not provide any visual cues: they only had auditory information to understand speech. Convenience of testing was another strength of the condition, as it did not require additional devices for the participants to wear. Weaknesses of the condition, on the other hand, included boredom, no provision of visual information, unrealistic testing environment, and noise. Since no visual cues were presented as part of this condition, participants thought that the test would not be able to accurately assess their real-world speech-in-noise performance. For the VSHMD condition, both groups reported the following strengths: less effort to hear, excellent audio and visual quality, excellent reality reflection, feeling present in the environment, and increased concentration during testing. Utilizing visual cues during testing helped the participants exert less effort to understand speech in the presence of noise. Excellent audio and visual quality and reality reflection allowed them to feel present in the VS during testing. However, the headset was heavy to wear, which the participants thought could possibly affect the test results. In terms of weakness, they mentioned that individuals who are not familiar with the HMD system might have difficulty performing the test  and that visualization provided as part of this condition might distract individuals.In our study, speech recognition improved with the provision of visual information, regardless of the presence of hearing loss. Hearing aids facilitated better speech recognition with lower listening effort for hearing aid wearers. All of these findings are consistent with previous literature -49. AfteOur study is meaningful in terms of diversity of participant characteristics, a relatively simple test environment, and a more naturalistic stimulus. Most studies utilizing VR for speech performance recruited individuals with NH and HI ,50-52 anIncorporation of visual information into speech testing can be beneficial for both patients and professionals. Since communication entails visual and auditory information, this type of testing could assess communication difficulties in conjunction with speech recognition performance more accurately. Patients would be more engaged in testing since the test is more interesting, as reported on the questionnaire. For hearing aid users, reality-reflected test results could foster realistic expectations, ownership of hearing loss, and better optimization of the devices. This would lead to increased satisfaction toward the device and reduced hearing aid return and discontinuance rate. If hearing aid wearers experience higher device satisfaction and perceived hearing aid benefit, the number of clinic visits for further adjustments would also decrease, which can be a critical issue for individuals who live far away from hospitals and clinics.Although a VS is shown to be beneficial for speech recognition in noise in this study, ample work is still needed to address some limitations of our research. Each K-HINT list was broken down into two separate lists so that hearing aid users could complete tests under unaided and aided conditions. It is highly likely that phoneme distribution was affected during this process and, therefore, test materials with more sentence lists need to be used for subsequent studies. The weight of the headset also needs to be improved. The authors believe that it is crucial to not only examine the effect of visual cues on speech performance but to test the device that will be used, as it could be one of many factors that professionals and patients would consider before employing and performing the test in clinics. The weight of the system was reported to be heavy on the questionnaire and was mentioned as a weakness of the VSHMD condition. Use of a lighter device could possibly address this concern. Another concern was that individuals who are unfamiliar with the HMD system might have difficulty performing the test. Designing user interfaces that are easy to use and providing tester assistance regarding the HMD system before and during testing could address the issue. It is also worth mentioning that in-depth investigation as to the amount contributed by each sensory modality for speech-in-noise performance is necessary. Gonzalez-Franco et al  examined


Mycoplasma hyopneumoniae (M. hyopneumoniae), many other viruses and bacteria can concurrently be present in pigs. These pathogens can provoke clinical signs, known as porcine respiratory disease complex (PRDC). A sampling technique on live animals, namely tracheobronchial swab (TBS) sampling, was applied to detect different PRDC pathogens in pigs using PCR. The objective was to determine prevalence of different PRDC pathogens and their variations during different seasons, including correlations with local weather conditions. A total of 974 pig farms and 22,266 pigs were sampled using TBS over a 5-year period. TBS samples were analyzed using mPCR and results were categorized and analyzed according to the season of sampling and local weather data. In samples of peri-weaned and post-weaned piglets, influenza A virus in swine (IAV-S), porcine reproductive and respiratory syndrome virus—European strain (PRRSV1), and M. hyopneumoniae were found as predominant pathogens. In fattening pigs, M. hyopneumoniae, porcine circovirus type 2 (PCV-2) and PRRSV1 were predominant pathogens. Pathogen prevalence in post-weaned and finishing pigs was highest during winter, except for IAV-S and A. pleuropneumoniae, which were more prevalent during autumn. Associations between prevalence of several PRDC pathogens, i.e., M. hyopneumoniae, PCV-2 and PRRSV, and specific weather conditions could be demonstrated. In conclusion, the present study showed that many respiratory pathogens are present during the peri-weaning, post-weaning, and fattening periods, which may complicate the clinical picture of respiratory diseases. Interactions between PRDC pathogens and local weather conditions over the 5-year study period were demonstrated.Besides  Mycoplasma hyopneumoniae (M. hyopneumoniae), influenza A virus in swine (IAV-S), and porcine circovirus type 2 (PCV-2) [Actinobacillus pleuropneumoniae (A. pleuropneumoniae) [Porcine respiratory disease complex (PRDC) is a multifactorial and complex disease in nursery and growing pigs , provoke PCV-2) ,6. Other ,6. Otheumoniae) ,6. InfecMycoplasma hyopneumoniae plays a major role within PRDC as the etiological agent of enzootic pneumonia, a chronic respiratory disease that mainly affects finishing pigs [Pasteurella multocida (P. multocida) and A. pleuropneumoniae [M. hyopneumoniae may act as a facilitator to other primary pathogens such as PRRSV [M. hyopneumoniae have been associated with more severe disease and higher mortality [Actinobacillus pleuropneumoniae, the etiological agent of pleuropneumonia in pigs, is the most important bacterial pulmonary pathogen in pigs worldwide. In its most virulent form, A. pleuropneumoniae induces severe, rapidly fatal pleuropneumonia in naïve pigs of all ages [A. pleuropneumoniae strains varies remarkably, ranging from acute disease with high mortality to more chronic respiratory problems without significant mortality. Animals may be carriers of A. pleuropneumoniae at the level of the tonsils and in chronic lung lesions.ing pigs ,8. Mycopeumoniae . Moreoveas PRRSV ,10, IAV-as PRRSV ,11,12, aas PRRSV ,14. The as PRRSV . PRRSV ias PRRSV ,19,20,21ortality ,22,23,24ortality ,26. The ortality . Recentlortality . Porcineortality . PCV-assortality . PCVAD iortality . This isortality , leadingortality ,34,35. Aortality . Porcineortality . Seropreortality . Dual inortality . Porcineortality . Virus tall ages . VirulenM. hyopneumoniae in pigs [M. hyopneumoniae, PRRSV , IAV-S, PCV-2, PRCV, PCMV), and a supplementary bacterial PCR (A. pleuropneumoniae), to detect seven different PRDC pathogens.Using conventional necropsy findings or serology is a relevant first step towards diagnosis of the complex combination of several PRDC pathogens. However, due to the absence of pathognomonic lesions involved and the variable interval between infection and seroconversion for each of these pathogens, it is frequently not easy to obtain a conclusive diagnosis. Therefore, direct detection of pathogens present through PCR techniques is currently used ,6,42,43. in pigs  was usedThe aim of the present study was to detect the prevalence of several respiratory pathogens in pigs with clinical signs of respiratory disease using the TBS sampling technique and to gain insights into seasonal variation and correlation with local weather conditions.M. hyopneumoniae and all other PRDC pathogens among the different age categories are given in M. hyopneumoniae-positive, increasing to 16.2% at 6–11 weeks of age. In the fattening period, sampled pigs with clinical signs of respiratory disease were 53.4% M. hyopneumoniae-positive.The prevalence data of A. pleuropneumoniae occupied an intermediate position with a prevalence of 24.7% at 3–5 weeks of age.During the peri-weaning period (3–5 weeks of age), most prevalent PRDC pathogens were IAV-S (28.4%), PCMV (18.2%), PRRSV1 (11.5%), and PRCV (6.8%). Other pathogens, such as PRRSV2, PRRSV1,2, and PCV-2 were much less prevalent. The secondary pathogen A. pleuropneumoniae rose from 24.7 to 32.1% during the post-weaning period. During the post-weaning period (6–11 weeks of age), predominant PRDC pathogens were PCMV (26.7%), PRRSV1 (25.5%), IAV-S (20.5%), and PCV-2 (11.4%). Other pathogens, such as PRRSV2, PRRSV1,2, and PRCV had a rather low prevalence (<3.0%). Prevalence of A. pleuropneumoniae further increased towards 47.9% during the fattening period.During the fattening period (12–25 weeks of age), prevalence of several PRDC pathogens showed a clear shift. PRRSV1 prevalence remained stable at 28.5%, although other PRRSV strain types also gained importance with PRRSV2 at 5.3% and PRRSV1,2 at 1.9% prevalence. PRCV and PCMV prevalence further decreased to 1.2% and 6.8%, respectively. Prevalence of IAV-S decreased to 11.4%, whereas PCV-2 increased to 27.1%. Prevalence of M. hyopneumoniae, PRRSV–IAV-S, PRRSV–PCV-2 and M. hyopneumoniae–IAV-S within the double infections and PRRSV–M. hyopneumoniae–IAV-S and PRRSV–M. hyopneumoniae–PCV-2 within the triple infections.Prevalence of different double and triple PRDC major pathogen interactions are given in Effect of season on prevalence of different PRDC pathogens or combinations of pathogens in different age categories are given in M. hyopneumoniae and other PRDC pathogens could be observed. At 6–11 weeks of age, several pathogens had a seasonal variation in occurrence. Actinobacillus pleuropneumoniae had the highest prevalence during summer (S3), whereas IAV-S was most prevalent during autumn (S4). For the viral agents PRRSV1 and PCMV, the highest prevalence occurred during winter (S1).At 3–5 weeks of age, no seasonal effect on prevalence of M. hyopneumoniae, showed seasonal variations. These combined infections included M. hyopneumoniae–PRRSV1 (7.2%), M. hyopneumoniae–PCV-2 (5.7%), M. hyopneumoniae–IAV-S (3.7%) and M. hyopneumoniae–PRRSV1–PCV-2 (3.3%). For most pathogens, highest prevalence could be observed in winter (S1), except for PCMV , A. pleuropneumoniae, and the combined infection of PRRSV1–A. pleuropneumoniae . During the fattening period, both single PRDC pathogens and combined infections, including The most relevant associations (expressed as odds ratio (OR) with the 95% confidence intervals between brackets) between prevalence of different pathogens during the 5-year study in Belgium and the Netherlands and local weather parameters are presented in .10w) and average wind speed in the 10 weeks prior to sampling (WSavg.10w) were only positively associated with all pathogen prevalence with OR ranging from 1.280 (PRRSV1) to 1.918 (PCV-2) for WS.10w and OR ranging from 1.267 (PRRSV1) to 1.947 (M. hyopneumoniae–PCV-2) for WSavg.10w.Wind speed in the 10 weeks prior to sampling (WSdiff.10w) was negatively associated with PRRSV1 (OR = 0.921), PCV-2 (OR = 0.834), M. hyopneumoniae–PCV-2 (OR = 0.818), and PRRSV–PCV-2 (OR = 0.799).The difference between minimum and maximum outside temperature in the 10 weeks prior to sampling (Tdur.10w) was positively associated with A. pleuropneumoniae (OR = 1.164) and negatively associated with PRRSV1 (OR = 0.911) and PRRSV–PCV-2 (OR = 0.817).Duration of sunshine in the 10 weeks prior to sampling (Smin.10w) was negatively associated with A. pleuropneumoniae (OR = 0.940), and positively associated with PRRSV1 (OR = 1.020), PCV-2 (OR = 1.030), and PRRSV–PCV-2 (OR = 1.048).Minimal relative humidity in the 10 weeks prior to sampling (RHM. hyopneumoniae–PCV-2 (OR = 1.026).Wind direction in the 10 weeks prior to sampling (WD.10w) was negatively associated with PRRSV1 (OR = 0.981) and positively associated with M. hyopneumoniae, besides other pathogens associated with PRDC, such as Streptococcus suis, A. pleuropneumoniae, P. multocida, DNT-positive P. multocida, Glaeserella parasuis (G. parasuis), Mycoplasma hyorhinis (M. hyorhinis), Mycoplasma hyosynoviae, PRCV, and PCMV [Porcine respiratory disease complex remains one of the most important health concerns with a high economic impact for pig producers worldwide. The disease involves multiple viral and bacterial pathogens together with several non-infectious factors, such as ventilation, housing conditions, and management, leading to respiratory distress in pigs ranging from the peri-weaning period (3–5 weeks of age) over the post-weaning period (6–11 weeks of age) to the finishing stage (12–25 weeks of age). Interaction between both infectious  and non-infectious factors may all contribute to the development and severity of the respiratory disease . The mosand PCMV ,48.M. hyopneumoniae could be performed using clinical signs, slaughterhouse checks of affected lungs [Detection of the etiologic agents of PRDC has long been difficult, especially due to the wide variety of diagnostic approaches applied in practice. Diagnosis of ed lungs ,50, seroed lungs ,50, direed lungs  or PCR ted lungs ,52. As fed lungs . AlthougM. hyopneumoniae at an early age [Polymerase chain reactions and real-time PCR tests have been developed for several pathogens involved in PRDC and are characterized by their high sensitivity and ease of use. In combination with a reliable sampling technique, such as TBS, these detection methods based on PCR have been able to detect arly age ,46 and iarly age ,54.M. hyopneumoniae, which is in accordance with previous reports applying the same sampling technique [M. hyopneumoniae, several other PRDC pathogens may be involved in the clinical picture of coughing piglets at 3–5 weeks of age, such as IAV-S, PRRSV1, PRCV, and PCMV, whereas the prevalence of PCV-2 is rather low at that stage. From a bacterial perspective, A. pleuropneumoniae is present in a quarter of the pigs sampled. These observations are in accordance with Sunaga et al. (2020) [A. pleuropneumoniae, Bordetella bronchiseptica, P. multocida, M. hyopneumoniae, M. hyorhinis), and viral agents  in some of the farms included in the study. Comparison of prevalence data is however not possible due to the low sample number  in this study [The results from the current study in 974 pig farms clearly demonstrate that pigs can be infected at an early stage with echnique . However. (2020)  who obseM. hyopneumoniae detection and prevalence only, the current study clearly demonstrates that M. hyopneumoniae is in many cases combined with other pathogens related to PRDC. The demonstrated presence of M. hyopneumoniae at an early stage (pre-weaning or post-weaning) might significantly impact the clinical course of other PRDC pathogens such as PRRSV [In contrast to previous studies ,46,53,54as PRRSV ,10, IAV-as PRRSV ,11,12, oas PRRSV ,15.M. hyopneumoniae and both PRRSV1 and PRRSV2 doubled in prevalence as compared to peri-weaned piglets (3–5 weeks of age), together with PCMV and A. pleuropneumoniae that showed a more moderate increase. In contrast, PRCV rapidly decreased during the post-weaning period. The prevalence of PCV-2 increased over four times during the post-weaning phase, indicating that PCVAD became more prominently involved in respiratory problems during this phase. Besides single infections with one of these PRDC pathogens, several combined double and triple infections , some clear differences in PRDC pathogen prevalence could be observed. fections  could alM. hyopneumoniae, PRRSV1, PRRSV2, and PCV-2, together with A. pleuropneumoniae and to a lesser extent IAV-S. The high prevalence of M. hyopneumoniae is of particular interest and may be partially explained by the long duration of pathogen persistence in the respiratory tract of the infected pigs. Previous studies have detected M. hyopneumoniae up to 254 days post-infection in deep laryngeal swabs using a PCR technique [M. hyopneumoniae infection status revealed that both age and type of production system had an impact on infection rate and pathogen prevalence [M. hyopneumoniae infection on one-site farms occurs earlier, while on two- and three-site farms occurs later but spreads faster, suggesting that contact between animals of different age favors the transmission. However, in the present study, data on the type of production system were not recorded. Nevertheless, the impact of age was similar in our study, since the prevalence of M. hyopneumoniae is substantially higher in the fattening pigs as compared to peri-weaned or post-weaned piglets with clinical signs of respiratory disease [M. hyopneumoniae during the post-weaning period or the early fattening period can excrete the pathogen for the entire fattening period, thus, increasing the probability of detection when pigs are sampled during an episode of respiratory problems. This is in contrast with other pathogens such as IAV-S that have a rather short period (max. 6–8 days) of detection at the level of the respiratory tract [During the fattening phase, the most prominent PRDC pathogens in pigs with clinical signs of respiratory disease were echnique . Recent evalence . Infecti disease . Therefory tract ,58. The ry tract . As repory tract .A. pleuropneumoniae at the highest level in summer (S3), IAV-S in autumn (S4) and both PRRSV1 and PCMV in winter (S1). In practice, it is well-known that respiratory problems related with A. pleuropneumoniae frequently occur at the change of seasons, especially with warmer days and colder nights, as might happen in our region at start of spring  and the end of summer , which explains the higher prevalence in these two seasons in our study. On the contrary, IAV-S occurs later in the year, when weather conditions turn cold and wet, which is the case in autumn (S4). In the colder winter months, PRRSV1 and PCMV seem to circulate more pronouncedly. The same pattern continues in the older pigs during the fattening period (12–25 weeks of age), where most PRDC pathogens and several combined respiratory infections are highly prevalent during winter (S1). Only exceptions from this pattern are PCMV (S4) and infections involving A. pleuropneumoniae, which are again more prominent during late summer (S3), as previously discussed.In the peri-weaned piglets, no effect of season on prevalence of PRDC pathogens could be observed. Presence of PRDC pathogens at that age is mainly determined by the infection status of their dam and outside conditions have very little impact on infection status at that age. In contrast, in post-weaned piglets, single PRDC pathogens are affected in their seasonal prevalence, with min.10w), temperature difference between minimum–maximum temperature (Tdiff.10w), wind speed (WS.10w), average wind speed (WSavg.10w), wind direction (WD.10w) and duration of sunshine (Sdur.10w). Apparently, the weather conditions in the 10 weeks prior to sampling have the largest impact on pathogen prevalence. Another interesting observation is that from all PRDC pathogens detected in prevalences higher than 5%, prevalence of M. hyopneumoniae and PRRSV is most frequently impacted by weather conditions. In a Spanish study [M. hyopneumoniae dynamics was also explored. This study revealed the higher the precipitation rate, the higher the probability of being M. hyopneumoniae nPCR-positive on nasal swabs, whereas the lower the temperature, the higher the probability of being M. hyopneumoniae seropositive. From a seasonal perspective, animals born in autumn and reaching slaughter in spring had the highest probability of being infected by M. hyopneumoniae and the highest probability of being M. hyopneumoniae seropositive [M. hyopneumoniae and PRRSV, were capable of spreading pathogens between herds via airborne route. Conditions common to both pathogens include cool temperature and specific wind direction, and more specifically low sunlight levels, low wind velocity in combination with rising humidity and air pressure [Several climatological parameters were significantly associated with PRDC pathogen prevalence. The most prominent parameters are relative humidity  available for sampling, presence of clinical signs of respiratory disease (coughing), and no use of antimicrobials active against the year . In totaTBS sampling was performed as previously described ,46. BrieM. hyopneumoniae, PRRSV (including differentiation in European (PRRSV1) and North-American (PRRSV2) or combined European and North-American strain type ), PCV-2, IAV-S, PCMV, and PRCV. A second PCR for bacterial species (A. pleuropneumoniae) was run on the same samples. The test was an App apxIV-PCR . It was a specific 414 bp-target, which had been tested for the detection of App serotype 1 to 19. Specificity was tested against the following species: Glaesserella parasuis serotypes 1–15, Actinobacillus porcitonsillarum, Actinobacillus suis, Actinobacillus minor, Actinobacillus indolicus, Actinobacillus porcinum, Actinobacillus equuli, Actinobacillus lignieresii, Mannheimia haemolytica, Pasteurella multocida, and Streptococcus suis. Analytical sensitivity was 1000 GE/mL. PCR results were reported as negative or positive for the presence of the different PRDC pathogens.The material collected by the TBS was processed according to Strait et al. (2008) . A multiM. hyopneumoniae and other PRDC pathogens sampled, herds were categorized for seasonality based on date of sampling. Seasonality was implemented as the following: S1—winter , S2—spring , S3—summer , and S4—autumn   .http://www.knmi.nl/klimatologie (accessed on 16 October 2016)).Climatologic data collected are presented in Besides the climatologic data observed on the day of sampling, a rolling average of the data over a 1-, 2-, 4-, and 10-week period were calculated for all sampling days throughout the 5-year study period.The effect of season on the prevalence of PRDC pathogens was investigated with logistic regression mixed models with a random effect for herd. The overall effect of season was tested with the likelihood ratio test, and all pairwise comparisons between seasons were performed on the log odds ration scale with Wald tests  and withThe effects of the climate parameters on the prevalence were investigated by fitting logistic regression mixed models with herd as random effect. The models were fitted for each combination of pathogen and climate parameter. The significance of the effects was tested by means of Wald tests. Given the large number of tests, false positives were controlled with the method of Storey (2003)  for contAll statistical analyses were performed in the statistical software R  (R Core In conclusion, the present study showed that many respiratory pathogens are present during the peri-weaning, post-weaning, and fattening period, which may complicate the clinical picture of respiratory disease. Moreover, interactions between these PRDC pathogens, season, and local weather conditions could be demonstrated over the five-year study period.


Temporarily extending retention of newly differentiated effector TCs, mediated by sphingosine-1-phosphate receptor-1 expression, mitigated any negative effects of swelling by allowing facilitation of activation to outweigh increased access to exit areas. These results suggest that targeting temporary effector TC retention and egress associated with swelling offers new ways to modulate effector TC responses in, for example, immuno-suppressed patients and to optimize of vaccine design.Swelling of lymph nodes (LNs) is commonly observed during the adaptive immune response, yet the impact on T cell (TC) trafficking and subsequent immune response is not well known. To better understand the effect of macro-scale alterations, we developed an agent-based model of the LN paracortex, describing the TC proliferative response to antigen-presenting dendritic cells alongside inflammation-driven and swelling-induced changes in TC recruitment and egress, while also incorporating regulation of the expression of egress-modulating TC receptor sphingosine-1-phosphate receptor-1. Analysis of the effector TC response under varying swelling conditions showed that swelling consistently aided TC activation. However, subsequent effector CD8 LNs contain compartments populated by T cells (TCs), B cells, fibroreticular cells (FRCs) and lymphatic endothelial cells (LECs) ,2. When + TCs) or class II (MHCII) (CD4+ TCs) molecule [TCs and B cells mainly enter LNs by transmigrating from blood vessels in the paracortex, while lymph-borne DCs migrate into the paracortex across the sub-capsular sinus (SCS) floor ,4. Typicmolecule ,6. With molecule .The mechanisms driving LN swelling include DC presence, B cell signalling and trapping of non-activated TCs –11. RegaBetween 2 and 5 days after immunization, the antigen-presenting DC (agDC) number in the LNs peaks, TC activation and proliferation is underway and TC egress increases three- to sixfold ,11,20,211r) expression and chemokine signalling axes. After entering the LN, TCs express S1P1r at low levels but begin S1P1r re-expression after 2 h [1r expression is reciprocally regulated by CD69, an early TC activation marker. This mechanism contributes to the initial decrease in TC egress, termed LN shutdown, and later to the specific retention of activated TCs [1r, facilitating egress [Throughout these processes, TC egress is modulated by sphingosine-1-phosphate-1 receptor  that could describe macro-scale geometric changes, micro-scale TC and DC interactions and capture emergent behaviour by modelling the probabilistic behaviour of thousands of cells. Beyond the desire for a better understanding, we aim to provide a means for designing experiments that explore potential therapeutic means of modulating LN swelling.Fixed-volume ABMs have provided insight into interactions relevant to vaccine design; for example, the effects of antigenic peptide separation on TC activation, influential aspects of TC–DC interaction and memory TC production –33. An AIn summary, the careful trafficking and coordination of immune cell movements in the LNs suggest that LN swelling may significantly impact the adaptive response. We developed a computational ABM to investigate this hypothesis. The results suggest an important role for regulating early effector TC retention to maintain the benefits of LN swelling on overall effector TC response.. 2. 2.1R0 = 200 µm, derived from confocal images of murine LNs [c). For each grid compartment, we tracked which region of the paracortex was represented, such as ‘exit’, ‘boundary’ or ‘outside’.We aimed to replicate a murine LN by integrating experimentally obtained parameters. The paracortex was modelled as a sphere with initial radius rine LNs . Geometr. 2.2V at time t as a sigmoidal function of the number of TCs present (Nt), constrained by maximal swelling (Vmax). Parameter Tmid determines the required number of TCs to reach half-maximal swelling, which we initially estimated as a doubling of the baseline number of TCs. Slope parameter (l) determines curve steepness and thus the rate of change in volume around Tmid,a; electronic supplementary material, figure A, S1 file). Initial TC increase is permitted without triggering significant swelling, reflecting initial inhibition of stromal cell proliferation by secretion of interferon type 1 [We collected data from murine experiments regarding change in LN mass and volume, TCs, structural cells, migrating DCs, TC recruitment and TC egress following antigenic stimulus application ,12,19,20n type 1 . A delayn type 1 ,40.. 2.3Tres) defined to range from 6 to 24 h and a constant TC-to-compartment ratio assumed . In accordance with HEV images, 90% of TCs entered at ‘entry’ compartments designated as the inner half of the paracortical radius [Under baseline conditions, the TC recruitment rate was specified as 2000 TCs/hour, with the naive TC transit time (l radius . RemainiTin), acute TC recruitment changes due to inflammation-induced signalling cascades at the HEVs were incorporated using the inflammatory index, IF. This index affects TC influx when antigenic presence D ) rises above threshold T1, which is the minimal DC number required to elicit a response [IF increases proportionally with antigenic presence by a recruitment factor (RF) up to a maximum inflammation-induced TC recruitment, threshold T2 (equation (2.4)). The volume of the entry grids is representative of blood vessel volume (VB), which changes proportionally with paracortical volume. We assumed that the TC recruitment rate (Tin) is additionally influenced proportionally by TN is the initial TC number, Tres is the naive TC transit time, FI is the inflammatory index and tN, LN volume and, consequently, Tin remained stable in the absence of antigenic stimulation. Threshold values for T1, T2 and FR were estimated from initial TC recruitment rate changes due to inflammation, while considering changes due to HEV growth and agDC number present [IF was calculated asNDC is the number of agDCs present, D is the sum of MHCII carried by each agDC and Recruitment Factor RF is an estimated increase in recruitment rate.When calculating the TC recruitment rate  is designated a default value of 1 and overall probability of TC egress (E) when entering an exit area is defined as E = eP.SP, where eP was experimentally determined to maintain influx and egress equilibrium under non-inflammatory conditions. We altered SP under three conditions . Following TC entry into the paracortex S1P1r remained downregulated (SPin = 0.1) for 45–180 min, before re-expressing due to low paracortical S1P concentration [1r (SPinflam = 0.4) on all TCs when sufficient antigenic presence (summation of MHCII) was detected, estimated to correspond to 6 h post-agDC appearance. Activation-induced TC S1P1r downregulation was represented by decreasing S1P1r expression 10-fold when TCs initially activated (SPact = 0.01), increasing S1P1r expression as TCs differentiated into early effector TCs (SPearly = 0.4) and further increasing expression when effector TCs underwent eight or more divisions (SPlate = 1) [Relative TC expression of S1Pntration . An ‘LN ate = 1) ,44,45.. 2.53 that initially occupied 55% of the total paracortex volume, approximately 5 × 104 TCs in our hemispheric model [Fcog) was derived from in vivo reports with default 1 × 10−4, resulting in approximately five cognate TCs at initiation [Bmax). The total number of DCs is calculated as a proportion of TCs (DCϕ), with a default value of 0.04 (approx. 2500 DCs). Each agDC presented a decaying MHC signal, and during interactions cognate TCs gained ‘stimulation’ (S) at rate κs, proportional to MHCs presented, while losing stimulation at rate λS. Similar to previous models, the probability of TC activation and, after a minimum of four proliferations, differentiation into effector or memory TCs was determined as a sigmoidal function of accumulated stimulation [TCs were modelled as spheres of volume 150 μmic model . The freitiation . DCs wermulation ,35,47. S. 2.6https://github.com/johnsara04/paracortex_model_johnson19.We built a class-based ABM  in Java using RepastSimphony (repast.sourceforge.net) with repeated rules each time step . Further. 2.7We estimated our parameters from published studies with inflammation-induced mice or previous relevant models . To ensure awareness of influential but uncertain or biologically unconstrained parameters, we carried out a global sensitivity analysis. We used Latin Hypercube sampling to select 300 parameter combinations, simulated each set three times and recorded the TC number . Partial rank correlation coefficients (PRCCs) were calculated between each parameter and output for each day (3–13), assuming monotonic relationships . We repo. 2.8in vivo and/or in vitro experiments, holding our parameter selection constant, aside from a single parameter. In each scenario, we compared the effects on TC activation and CD4+ and CD8+ effector TC response with relevant published studies. We inhibited S1P1r downregulation on activated TCs as carried out by Gräler et al. [et al. [et al. [et al. [et al. [et al. [et al. [To ensure that we did not overfit the model to one swelling scenario, we simulated four experiments that mimic r et al.  and Lo e [et al. . We vari [et al.  and Obar [et al. . We vari [et al.  and Mart [et al. , and we  [et al. .. 3. 3.1n = 200) of 13.1 µm min−1, reaching up to 24 µm min−1 (a), in line with murine in vivo measurements [n = 16 000), ranging from 20 min to greater than 60 h (b), in line with observations that 74% of CD4+ TCs and 64% of CD8+ TCs transit murine LNs within a day [c) illustrated the maintenance of random walk behaviour [2 min−1, which is within the 50–100 µm2 min−1 range observed in mice [We confirmed that the calibrated model produced an average TC velocity . TC numbers began to increase approximately 6 h after initial agDC entry, and by day 11 had returned to within 15% of pre-stimulus values (b), in line with temporal responses observed in vivo [in vivo reports and cell-culture models [+ TCs appeared 1–1.5 h before CD8+ effector TCs . As observed in vivo, the peak cognate CD8+ TC number was an order of magnitude higher than that of CD4+ TCs [b). An increase in TC egress rate peaked a day later than the increase in TC entry rate , corresponding well with in vivo observations [TC responses to agDC stimuli corresponded well to data from s values b, in lin in vivo ,20. The e models ,63. Effector TCs h,i. As oCD4+ TCs ,65. The try rate f,j, corrrvations ,66.Figu. 3.2in vivo and in vitro experiments resulted in reasonable TC behaviour. For example, preventing S1P1r downregulation post-antigenic stimulus detection in silico reduced activated TC number by 60–81% (a). A study transferring activated TCs that over-express S1P1r into mice LNs, removing S1P1r-mediated retention, resulted in 90% less activated TC retention than in control mice when measured 15 h later (figure 5b [1r showed a 40% reduction in activated TCs post immunization (figure 5c) [Holding the default parameters and varying a single parameter at a time to mimic y 60–81% a. A studigure 5b ). A studgure 5c) . See elecog, TDCin and Vmax. The unconstrained parameters used to describe signal integration and parameterize activation or differentiation probability curves were not identified as significantly influential in determining target outcomes  .The global parameter sensitivity analysis indicated that the dominant parameters in determining the target outcomes of TC activation, total TC effectors and TCs exited were F. 3.3Vmax) was varied from 1 to 2.8, the activated TC number doubled and positively correlated with Vmax  (a). The total number of effector TCs decreased by 15% (b) and negatively correlated with Vmax  but the number of effector TCs that exited by day 10 did not significantly vary .When maximal swelling ( < 10−5) a. The tod by 15% b and neg+ TCs present decreased by 25% (c), negatively correlating with Vmax  but there was no change in the number of exiting cognate CD8+ TCs . Conversely, the number of cognate CD4+ TCs that left the paracortex by day 10 increased by 30% and positively correlated with Vmax  (d) but cognate CD4+ TCs present did not vary significantly .Assessment of TC subgroups showed that the total cognate CD8d by 25% c, negati= 0.001) d but cogVmax, meaning that the absolute number of cognate TCs entering increased with swelling (e). TC egress rate increased with Vmax from day 3 to day 6 (f). Increased TC activation but decreased effector TC number remained when LN volume increased as a linear function of TCs .The peak TC recruitment rate positively correlated with swelling e. TC egrto day 6 f. Increa. 3.4Vmax = 1.20, 2.0 and 2.5). We found that there was no decrease in the mean number of agDCs that each cognate TC contacted on all days (a). We also found a slight increase in the number of contacts by day 3, a time point that corresponds with peak swelling. The mean number of short contacts by non-cognate TCs decreases with swelling (b). These results suggest that there is no decrease in the availability of DCs to cognate cells with swelling.We then analysed the mean number of interactions with DCs by cognate and non-cognate TCs present each day from day 1 to day 6 at different maximal swelling  while applying a lower (8 × 104 TCs) or higher (13 × 104 TCs) Tmid, making swelling occur relatively earlier or later (a). Regardless of Tmid value, at least 40% more activated TCs were recorded with a large Vmax compared with a small Vmax (b). With an earlier (low Tmid) and larger swelling, the total number of effector TCs and effector TCs exited dropped significantly (p < 0.05) (c). However, with later swelling (high Tmid), a larger swelling no longer reduced effector TC number. This altered effector TC response was due to a change in cognate CD8+ TC number, which showed the same pattern of results (e). There was no change associated with Tmid in cognate CD4+ TC response (f). Varying maximal swelling and Tmid over a wider range showed that the positive correlation of Tmid with effector TCs exited was only significant with a larger swelling (Vmax = 2.5) (d), likely due to the greater impact of varying Tmid with larger swelling (a).We carried out simulations with a small or large maximal swelling  c. Howeve results e. There response f. Varyinx = 2.5) d, likelyswelling a.Figure. 3.61r downregulation by lowering SPearly from the estimated default value of 0.4, a sustained increase in total TCs resulted, despite the action acting on early effector TCs only (a). Unlike during simulations with default SPearly . Reducing SPearly from 0.4 to 0.05 doubled the number of effector TCs exiting and increasing SPearly to 0.8 halved the number (b).When we increased S1PTCs only a. Unlike SPearly , effectoe number b.Figure+ and CD8+ effector TCs that exited the paracortex by day 10 doubled when SPearly was decreased from 0.4 to 0.05 . This indicated that CD4+ TCs do maintain further proliferative capacity in the model.When analysing the TC sub-populations, both CD4 to 0.05 c,d. Thisearly was decreased, but overall decreased with swelling; therefore, this was not a driving factor of increased effector TC number (e). Implementation of an alternative model with non-specific constraint of TC egress by reducing expansion in the exit area also resulted in increased effector TC exit but produced unrealistic prolonged swelling above a 1.4-fold swelling .The number of TCs contacted by DCs increased as SPC number e. Implem. 3.7inflam from 0.1 (90% downregulation) to SPinflam = 1 (no shutdown). We permitted a doubling of LN volume. Increasing non-specific S1P1r downregulation from 60% to 90% resulted in a sharp, threefold higher peak in the total number of TCs (a), which is less physiologically realistic than with our default parameters. As SPinflam decreased, TC activation increased  (b), but no trend with total effector TCs was identified (c). We found no correlation between increased LN shutdown and the mean number of contacts with DCs by cognate TCs present at day 3 but a positive correlation with DCs contacted by non-cognate TCs  (d).We also varied the degree of initial LN shutdown, by varying SPr of TCs a, which  = 0.01) b, but noentified c. We fou 0.0017) d.Figure. 3.8b). With Vmax = 2.5, we recorded a mean 33% fall compared with a 5% decrease with 10-fold higher cognition . We repeated the simulations with increased early effector TC S1P1r downregulation (SPearly = 0.1). This resulted in swelling of 2.0- or 2.5-fold benefiting the response. Assessment of TC and DC interactions showed that this was not due to an increase in contact with DCs (c).Simulations using a 10-fold lower cognate TC frequency showed a larger decrease in effector TC number with swelling than the simulations with default cognition. With lower cognition, we observed a mean 73% fall with a twofold swelling, compared with a mean 17% decrease with 10-fold higher cognition b. With Vwith DCs c.Figure. 4In this work, we aimed to better understand the effects of LN swelling in the formation of TC responses and identify key features that can influence TC behaviour. Our study builds on work using ABMs to investigate the impact of signal integration kinetics, TC migration and interaction dynamics on TC response with a focus on macro-scale alterations and accompanying changes in egress and recruitment –31,33,35in vivo TC recruitment studies [We found that permitting LN swelling consistently aids TC activation but allowing increased swelling can inhibit subsequent effector TC response if it resulted in increased opportunity for effector TCs to egress prior to optimal proliferation. Our modelling rules meant that LN swelling contributes to increased TC recruitment in a positive feedback loop and therefore to a higher absolute number of cognate TCs entering into the paracortex, increasing TC activation probability, in agreement with  studies . In our 1r-mediated retention of newly differentiated effector TCs increased effector TC production in scenarios where effectors egress prior to reaching sufficient proliferation. The increased production was not due to increased contact with DCs (e), and non-specific TC retention in the first few days had no impact on effector TC response , activation and differentiation probability curves , TC recruitment and paracortical swelling . The sensitivity analysis showed that the parameters populating activation and probability curves were not highly influential, and the influence of signal integration patterns has been the focus of previous modelling studies [in vivo experiments that were not used in parameter estimation.Our model contains unconstrained parameters that relate to signal gain and loss  could also significantly improve the representation of swelling, and thus TC egress and retention. It has been well established that changes in hydrostatic and oncotic pressure differences across nodal blood vessel walls can reverse the net fluid exchange ,73. Affe. 5Our results suggest that, although permitting LN swelling aids TC activation, events that increase opportunity for TC egress prior to optimal proliferation, such as early LN swelling, inhibit effector response. We found that temporary retention of newly differentiated effector TCs boosted effector TC response. This effect is particularly of interest when the initial TC response is small, for example in immuno-suppressed patients, or desirable, such as when optimizing vaccine design to minimize antigen dose. Although permanent blockade of effector TC egress has been used clinically to treat multiple sclerosis, temporary retention of effector TCs to boost effector TC production presents a novel mechanism to enhance immune reaction. Further clinically relevant insights include identification of the importance of alterations in TC egress with swelling, implying that the manipulation of factors involved in the underlying swelling mechanisms is a worthwhile clinical strategy. Variability in response among individuals is an accepted reality in immunology, and variations in ability to produce LN swelling (a readily measurable biomarker) could provide a means to project likely immune response. Our results also highlight the influence that retentive features, including factors such as chemokines, have on effector TC response, which may be more practical clinical targets to manipulate.


The Better hEAring Rehabilitation (BEAR) project aims to provide a new clinical profiling tool—a test battery—for hearing loss characterization. Although the loss of sensitivity can be efficiently measured using pure-tone audiometry, the assessment of supra-threshold hearing deficits remains a challenge. In contrast to the classical “attenuation-distortion” model, the proposed BEAR approach is based on the hypothesis that the hearing abilities of a given listener can be characterized along two dimensions, reflecting independent types of perceptual deficits (distortions). A data-driven approach provided evidence for the existence of different auditory profiles with different degrees of distortions. Ten tests were included in a test battery, based on their clinical feasibility, time efficiency, and related evidence from the literature. The tests were divided into six categories: audibility, speech perception, binaural processing abilities, loudness perception, spectro-temporal modulation sensitivity, and spectro-temporal resolution. Seventy-five listeners with symmetric, mild-to-severe sensorineural hearing loss were selected from a clinical population. The analysis of the results showed interrelations among outcomes related to high-frequency processing and outcome measures related to low-frequency processing abilities. The results showed the ability of the tests to reveal differences among individuals and their potential use in clinical settings. In current clinical practice, hearing loss is diagnosed mainly on the basis of pure-tone audiometry , 2010. TPure-tone audiometry is often complemented by speech audiometry , 2012, wIn Denmark, the Better hEAring Rehabilitation (BEAR) project was initiated with the aim of developing new diagnostic tests and hearing-aid compensation strategies for audiological practice. Although the assessment of individual hearing deficits can be complex, new evidence suggests that the perceptual consequences of a hearing loss can be characterized effectively by two types of hearing deficits, defined as “auditory distortions”  There is evidence from the hearing research literature that the considered test is informative  and reliable . (2) The outcomes of the test may be linked to a hearing-aid fitting strategy. (3) The outcome measures are easy to interpret and to explain to the patient. (4) The task is reasonably time-efficient or can be suitably modified to meet this requirement . (5) The test implementation can be done with equipment available in clinics. (6) The tasks are not too demanding for patients and clinicians. (7) Tests with several outcome measures are prioritized. (8) The language-independent tests are also prioritized. Although a large list of tests candidates was considered in an early stage, discussions among the authors and other BEAR partners to shorten the list led to the current proposal. Some classical tests were discarded because a suitable alternative was more promising. For example, the short-increment sensitivity index (SISI test) was discarded since there was a more informative candidate for measuring loudness perception.The selected test battery included measures of audibility, loudness perception, speech perception, binaural processing abilities, spectro-temporal modulation (STM) sensitivity, and spectro-temporal resolution. It was implemented and tested in older listeners with different hearing abilities (from mild to severe hearing losses) as a representative sample of the population of hearing-aid user candidates mainly affected by age-related hearing loss. The goals of the study were as follows: (1) To collect reference data from a representative sample of HI listeners for each of the selected tests, (2) to analyze the test–retest reliability of these tests, (3) to analyze the relationships between the different outcome measures, and (4) to propose a version of the test battery that can be implemented in hearing clinics.The test battery consisted of ten tests (9 tests besides the pure-tone audiometry). The outcomes of the proposed tests are divided into six categories. Although many of the tests included in the test battery are based on previous studies with normative data, a group of 11 young normal-hearing (NH) listeners were tested in the facilities of the Technical University of Denmark (DTU) and the University of Southern Denmark (SDU) to obtain reference data for this specific implementation of each of the tests. The summary statistics of the outcome variables from The examiners kept track of the time used by each of the participants in completing the test battery. In the case of unexpected events , these events were cautiously annotated for later investigation. Regarding the test procedure, additional repetitions of the threshold estimations were needed if: (1) a repetition was considered as an outlier ; or (2) the responses of the listeners during the tracking procedure were inconsistent or reached the maximum or minimum possible values. In that case, the measurement was considered an invalid or “missing” data point.The timing of the individual tests is shown in 2Seventy-five listeners  participated in the study, who were aged between 59 and 82 years (median: 71 years). Five participants were considered older normal hearing (ONH) with thresholds below 25 dB hearing level (HL) in the frequency range between 0.25 and 4 kHz in both ears and no larger than 40 dB HL at 8 kHz (PTA ≤ 22 dB HL)The participants were recruited from the BEAR database  have been linked to the concept of “hidden hearing loss” and synaptopathy  was defined by the expression 1:The procedure used here was a yes/no task using a single-interval adjustment matrix (SIAM) yes-no task procedure  was 11 kHz for the ONH listeners and 8 kHz for the HI listeners. The HI group showed larger variability compared to the ONH group (interquartile range: 6 vs. 10 kHz). The eAUD-HF test showed very good reliability . These results suggest that the FLFT paradigm might be a good time-efficient alternative to the traditional audiometry for measuring HF sensitivity. A recent study pointed out the importance of off-frequency listening and the role of the excitation of the basal cochlea when presenting narrow-band stimuli in high levels  spanned between 0 and 50, were fitted to a model of loudness as described in Oetting et al. . The outρ = 0.88;p < < 0.0001) even when looking at the HI group alone  despite the use of different stimuli and procedure.The results of the ACALOS outcome measures are shown in The average MCL estimate ranged between 74 and 83 dB HL in both groups and for both frequency ranges. The only appreciable difference between the two groups in terms of MCL was found at HFs and only in the right ear. The average slope of the loudness growth was slightly steeper for the HI listeners in the LF range (0.45 CU/dB for HI vs. 0.35 CU/dB for ONH) and substantially steeper in the HF range (0.8 CU/dB for HI vs. 0.45 CU/dB for NH). The average dynamic range was between 80 and 90 dB HL for the ONH listeners, and smaller for the HI listeners, especially at HFs (50.8 dB). Regarding the test–retest reliability, ACALOS showed an excellent reliability for estimating the hearing thresholds , good reliability for estimating the MCL , and very good reliability for estimating the slope . Overall, these results supported the inclusion of ACALOS in a clinical test battery, as it provides several outcomes . ACALOS also showed a high time efficiency (around 10 min per ear).The word recognition score with four unforced choices (WRS-4UFC) test was proposed as a systematic and self-administered procedure that allows the estimation of supra-threshold deficits in speech perception in quiet. The speech material was the same as the one used for standard speech audiometry  and 11.8 dB for the right ear (RE). The maxDS for both groups was close to 100%. However, the HI listeners showed larger variability, especially in the right ear (SD= 6.42%). In the analysis of the test–retest variability, the WRS-4UFC test showed poor to moderate reliability, especially at low levels . However, at the higher presentation levels  the standard error of the measurement was only 4% (1 word). Regarding clinical applicability, the WRS-4UFC needs to be compared to traditional speech audiometry to explore the influence of using closed- vs. open-set and forced- vs. unforced-choice test procedures on the results.The Hearing in Noise Test . The presentation level of the noise was set between 65 and 85 dB SPL to ensure that the noise was always presented 30 dB above the individual PTA. Each ear was tested individually. All participants were tested using the same list with the same ear. Since small differences across lists were found in Nielsen and Dau  for the right ear in both groups of listeners. According to Nielsen and Dau (+4dB: ICC = 0.57) indicated only moderate reliability of the HINT. The SRTN showed an SEM = 1.02 dB, which is below the step size of the test (2 dB). The SScore+4dB showed an SEM value of 7.94%, which corresponds to an error in one of the sentences. However, the reliability of the test can be improved by using an adaptive method as the one described in Wagener et al.  shows the sensitivity in terms of d', where the maximum value is d' = 3, . In the hypothetical case when all the catch trials are detected, the lowest d' value can be –0.3. The ONH listeners showed a high sensitivity in the LF condition (d' = 2.6) and a somewhat lower sensitivity in the HF condition (d' = 1.63) corresponding to 65% correct responses. The HI listeners showed a higher variability and a lower sensitivity in the LF condition (≈ 70% correct) and substantially lower sensitivity in the HF condition (0–50% correct responses). The threshold-tracking procedure (fSTM) showed results between –9 and –1.6 dB ML in the ONH group, whereas the HI listeners showed thresholds between –3.50 and –0.6 dB ML in the LF condition. Although the results of the fSTM LF condition were consistent with Bernstein et al. , the resThe extended audiometry in noise (eAUD) is a tone detection test intended to assess different aspects of auditory processing by means of a task similar to pure-tone audiometry. The tone is presented in the presence of noise and the listener has to indicate whether the tone was perceived or not. The aspects of auditory processing assessed here are (1) tone-in-noise detection and (2) spectral and temporal resolution.In pure-tone audiometry, a given patient has to detect the simple stimulus  in quiet aiming at estimating the hearing thresholds of the listener. A simple way to explore the supra-threshold performance is to perform a tone-in-noise detection test by presenting noise at supra-threshold levels and obtaining the masked thresholds. However, the characteristics of the noise such as bandwidth, level, or inherit modulations can affect the results. Moore et al.  proposedFrequency and temporal resolution are aspects of hearing that are fundamental for the analysis of perceived sounds. While NH listeners exhibit a frequency selectivity on the order of one-third of an octave when using isoinput levels  the threshold is expected to be approximately at the level of the noise, in the temporal and spectral conditions the thresholds should be obtained at a lower level, showing temporal masking release (TMR) and spectral masking release (SMR).fc, noise = 1.1ftone. In the eAUD-T condition, the modulation frequency of the noise was set to, fm = 4 Hz. The outcome measures of the eAUD are 1) the tone-in-noise threshold (TiN), (2) the temporal masking release (TMR), and (3) the spectral masking release (SMR). The first two reversals were discarded and the thresholds were the average of the last four‘reversals.The procedure used here was a yes/no task using a SIAM procedure  at LFs. The detection thresholds were in line with previous work with thresholds close to the noise presentation level (70 dB HL)  and tone-in-noise detection presented dichotically, i.e., with the tone in anti-phase across the two ears (SπN0).The BMR was assessed using the same method as the extended audiometry. Two measurements were required: (1) tone-in-noise detection presented diotically  and interquartile range (≈ 370 Hz) similarly in both groups. These results are in line with the ones reported in Füllgrabe and Moore . The IPDThe overall results from the binaural pitch test for the NH listeners showed >87.5% correct detection, whereas the HI listeners' results showed a higher variability, with an interquartile range from 70 to 100%. The test showed excellent reliability , which may be influenced by ceiling effects since 6 participants got 100% correct responses. Listeners reported a positive experience due to the test being short and easy to understand.0N0 condition thresholds to be similar to the noise presentation level . The variability of this condition was substantially lower than the SπN0, suggesting that the use of SπN0 can be sufficient and more informative. A similar reasoning has been recently reported in Grant et al. , and the correlation values are presented on the left-hand side of the figure. Two groups of correlated variables can be observed. The upper-left corner shows variables related to LF processing  and speech intelligibility in quiet. The bottom-right corner shows a larger group of correlated variables including HF processing, speech intelligibility in noise, and spectro-temporal resolution at HFs. The variables that are not significantly interrelated are shown in the middle part of The four factors resulting from the factor analysis showed 63% of explained cumulative variance. The variables with higher loadings (> 0.65) for each of the factors are shown in The first goal of the present study was to collect data from a heterogeneous population of HI listeners, reflecting their hearing abilities in different aspects of auditory processing. The current study was motivated by the need for a new dataset to refine the data-driven approach for auditory profiling. The dataset should contain a representative population of listeners and outcome measures  that may benefit from specific types of hearing rehabilitation toward a “stratified approach” , showed good to excellent test–retest reliability with all ICC values above 0.9, while other tests, such as the extended audiometry in noise and speech intelligibility in quiet, showed poor reliability. The selected tests were conducted in two sessions and the total time was, on average, 3 h including the instructions and interview. In realistic clinical setups, a subset of tests with high reliability and a reasonably low difficulty would need to be prioritized. For a clinical version of the test battery, other tracking procedures such as Bayesian functional information  can be found below: The studies involving human participants were reviewed and approved by Science-Ethics Committee for the Capital Region of Denmark H-16036391. The patients/participants provided their written informed consent to participate in this study.CRediT (Contributor Roles Taxonomy). RS-L: conceptualization, methodology, software, validation, formal analysis, investigation, data curation, visualization, and writing-original draft and editing. SN: investigation, validation, resources, formal analysis, visualization, and writing-original draft. ME-H-A: methodology, investigation, resources, and writing-review. MF and FB: conceptualization, methodology, supervision, and writing-editing. MW and OC: investigation, resources, and writing-review. TN: methodology, supervision, project administration, and writing-review. SS and TD: conceptualization, methodology, supervision, project administration, funding acquisition, and writing-review. All authors contributed to the article and approved the submitted version.Author contributions according to This work was supported by Innovation Fund Denmark Grand Solutions 5164-00011B (Better hEAring Rehabilitation project), Oticon, GN Resound, Widex, and other partners .RS-L was employed by the company Interacoustics A/S, Denmark. FB was employed by the company Oticon Medical, Denmark. SB was employed by company Oticon A/S. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Unilateral congenital atresia, a specific type of unilateral conductive hearing loss (UCHL) occurs in 1 in 1,500 births . It is cLocalization of sounds and understanding of speech in complex listening situations are reported to be impaired . GrammarApplication of a hearing implant for children with congenital UAA and for patients with acquired aural atresia has proven to be effective , 32. HowThis document does contain the following sections:- Causes for limited benefit of a BCD for congenital UAA.- Non-use.- Is age at intervention important for consistent use of BCD in UCHL?- Non-invasive bone-conduction hearing devices.- What to advice parents of children with UAA?- A multidisciplinary approach.Several differences between bone-conduction hearing and hearing with a normal-hearing ear exist. These differences might put constraints on adequate binaural processing. BCDs are limited in their dynamic range, which is typically <40 dB, whereas it is ~110 dB for the normal hearing ear. Furthermore, BCDs and VSB have a limited bandwidth (500 Hz−4 kHz), and a digital processing time of 3–14 ms. Therefore, BCDs provide less valuable and precise auditory information compared to the contralateral normal hearing ear. In addition, because bone-conduction sounds are effectively propagated by the skull bone, interaction of sounds might occur in the normal hearing cochlea between the air-bone signal and cross-stimulation caused by the BCD . ResultsA solid view on which children with UCHL benefit from interventions is needed , 46. ObjResearch into the effectiveness of amplification in children with congenital UCHL is scarce and there is limited information about the long-term use of BCDs. A long-term evaluation by Nelissen et al.  demonstrIt would be of high prognostic value to understand the reasons for the high proportion on non-use. Is gain/sound itself annoying? Is it the delay between the ears? Might there be a chance that we implant too late? Would non-use decrease if frequencies around 6–8 kHz are better amplified?We face several unanswered questions when dealing with congenital UCHL. One of the most important questions is whether there is an optimal window for the treatment of congenital UCHL. Recent work by Vogt et al.  demonstrChildren with congenital UCHL can still hear their own voice by bone- and tissue conduction. This input (own voice) might minimize detrimental effects of a “sensitive period” and might explain why relatively early implantation (at age 4 years) has no advantage compared to implantation later in life . Yet, anAlthough more limited in technical performance compared to implantable BCDs , non-inHopefully the development of new hearing implants for conductive hearing loss , 58, 59 Aiming for optimal care might seem trivial but we have to accept that the industry aims to sell as many implants as possible, that a more complex surgery suggests a better outcome and that the audiologist is aiming for the best possible aided thresholds. In order to realize optimal treatment, adequate information about the limitations and possibilities about monaural hearing should be provided by a multidisciplinary team. In order to limit overuse of medical treatment , this teAll authors contributed to the writing of the manuscript and all authors were involved in defining the topic.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.