Although a causal association remains to be determined, epidemiologic evidence suggests an association between hearing loss and increased risk of dementia. If we determine the association is causal, opportunity for targeted intervention for hearing loss may play a fundamental role in dementia prevention. In this discussion, we summarize current research on the association between hearing loss and dementia and review potential casual mechanisms behind the association . We emphasize key areas of research which might best inform our investigation of this potential casual association. These selected research priorities include examination of the causal mechanism, measurement of co-existing hearing loss and cognitive impairment and determination of any bias in testing, potential for managing hearing loss for prevention of dementia and cognitive decline, or the potential to reduce dementia-related symptoms through the management of hearing loss. Addressing these research gaps and how results are then translated for clinical use may prove paramount for dementia prevention, management, and overall health of older adults. Hearing loss is the leading potentially modifiable risk factor for dementia; up to 8% of global dementia cases are estimated as being attributable to hearing loss , 2020. FEven with our expanding knowledge of the association between hearing loss and dementia, significant gaps in our understanding persist. In this article, we aim to (1) provide a foundational understanding of hearing loss presentation and diagnosis; (2) review current hearing loss epidemiology (3) provide context to the existing research on the relationship between hearing loss and dementia to guide dementia prevention and intervention recommendations or research; (4) discuss the leading theories on the pathways behind the hearing-dementia association; and (5) present four crucial areas for future research. With the demographic changes in the coming decades, we conclude with calls for inter-disciplinary collaboration and posit a unique opportunity to alter the landscape of cognitive aging and dementia care. Understanding the role and presentation of hearing loss in the adult population allows for better appreciation of where the field of auditory science may fit into a broader picture of dementia prevention and interventions.The act of hearing involves two inter-related processes and components of the auditory system – the peripheral auditory system and the central auditory system  and addiThe peripheral auditory system includes the outer ear (pinna), ear drum (tympanic membrane), middle ear bones , and cochlea . These cThe most common clinical tool for measurement of peripheral hearing acuity in adults is pure tone audiometry , with reFollowing passage through the peripheral auditory system, the electrical signal created by the cochlea is sent to the auditory nerve where it is then decoded by the brain . CentralMeasurement of central auditory function is often completed through the presentation of speech within the presence of increasing volume of selected types of background noise  or specialized tests of central auditory processing ability that involve specific tasks like listening to degraded or temporally modified speech . HoweverAge-related hearing loss (ARHL), also known as presbycusis, accounts for the largest percentage of hearing loss cases around the world and presents as a gradual decrease in hearing ability. The outer hair cells and other sensory cells in the cochlea are progressively damaged and unable to regenerate . The resThe impact of a given pattern of hearing function as represented on the audiogram on communicative performance may vary widely from individual to individual . An indiHearing loss currently impacts an estimated 20% of the global population, or more than 1.5 billion people . By 2050Globally, the cost of unaddressed hearing loss is estimated at over $980 billion annually . EconomiThe prevalence of hearing loss varies by non-modifiable factors such as certain identified syndromes and genetic factors . AdditioAdditional potential causative risk factors for hearing loss across the life course have also been identified . While mHistorically, hearing loss has been considered a benign component of the aging process resulting primarily in impaired communication. However, research over the last few decades has highlighted hearing loss as a precipitating factor for additional functional and neuropsychiatric disorders in older adults and has spurred changes in thought within the medical and public health community . ImportaThe expected rise in dementia cases around the world requires action on dementia prevention and intervention across innovative and multi-disciplinary channels to meet the pressing societal and health needs. With no known dementia cure, epidemiologic research then seeks to discern risk factors associated with the progression of dementia pathology, progression of dementia symptoms, or with dementia diagnosis to delay or minimize the impact of clinical symptoms . If we cIn this review, we highlight evidence of the association and potential causal effect primarily within studies utilizing completed objective measures of auditory function . While consideration of self-reported hearing is important, it integrates aspects of not only peripheral auditory function but also of an individual’s perceived hearing and communication ability, incorporating environmental and communication demands, mental health, listening motivation and expectations, and central auditory function.Heterogeneity in study methodology and design creates challenges to synthesize data from hearing and cognition research. Heterogeneity exists across audiometric and cognitive parameters as well as sample sizes, populations studied, and consideration of confounders, to name a few. Within auditory science, heterogeneity includes aspects such as differing means to define hearing loss, pure tone frequencies used, or how hearing ability is categorized. For cognitive research, variability in the neurocognitive tests used, domains investigated, utilization of cognitive screeners, patient or physician report, and ways of defining cognitive change  all create obstacles for evidence synthesis.Lancet Commission  vs. consideration of those with a moderate or greater hearing loss (PTA > 40 dB HL) as the hearing-impaired group likely constitutes different comparison groups and underlying idea of what is a hearing “loss” across different studies.A previous meta-analysis  found thVaried measures of cognition used have also placed challenging demands on synthesis of prior results. A plethora of validated neurocognitive assessments exist both across cognitive domains and as global screeners. Variation in domain, mode of administration, if accommodations for hearing loss were considered, whether cognitive status was determined by provider or proxy report exist across studies, among others. While the importance of evaluating cognitive ability in multiple ways should not be ignored due to the complexity of cognitive processing and complex diagnostic presentation, synthesis of results across studies remains aloof.While an association between cognitive decline/dementia and peripheral auditory function is well established , the relPrior systematic reviews have revealed mixed quality and potential bias in previous work on central auditory function and cognition . Dryden early marker  as a measure of central auditory function. The DSI presents a meaningless but grammatically correct sentence to each ear simultaneously and the listener is to then identify the sentences, with designated systematically differing modes of reporting the sentence items . This diInvestigation of various means to define and measure central auditory function suggest an association with subjective memory complaints/impairment . In a smAcross measures of central auditory processing, an association has been observed between biomarkers such as CSF tau, cortical thickness and volumetric measures of AD-related brain regions , althougDue to low-risk auditory rehabilitation tools such as hearing aids, hearing loss in older adults is readily considered modifiable and therefore makes it a worthy target of interest among dementia risk factors. The current limited use of hearing aids and challenges with accessibility of hearing devices and services have been a focus of both health research and public policy in recent years , bringinThe complexities and interdependence between central auditory function and cognitive processing present challenges for causal inference. Therefore, current hypotheses of mechanistic pathways predominantly view peripheral hearing loss as a potential cause of dementia and consider central auditory function as a marker of cognitive decline. Current hypotheses of the causal mechanistic pathways have been well articulated in other works . ClarifyA growing body of evidence indicates prolonged sensory deprivation has an adverse effect on the brain, with enduring changes to brain structure and function. Due to auditory deprivation from ARHL, neural deafferentation, cortical re-allocation for support of other processes, and atrophy in brain regions important for speech perception processing may occur. The resultant reorganization may add to existing brain pathology  at the detriment of general cognitive performance by altering critical brain regions which could otherwise be utilized for higher-level cognitive processing. Reduced gray matter density and reductions in temporal lobe volume are observed in those with peripheral hearing loss , as prolWhile the sensory deprivation hypothesis suggests physical changes to the brain due to prolonged hearing loss which subsequently impacts cognitive processing, the information degradation hypothesis proposes the association stems from increased demands on cognitive processing in order to compensate for impoverished sensory input. The additional processing required to compensate for degraded auditory perception draws on the same resources needed for other higher-level cognitive processing and semantic encoding . These iAlternatively, both hearing loss and cognitive impairment may merely stem from the same underlying mechanism . Given tAPOE ε4) has shown no association with hearing loss  genetic determinants exist may provide further insight toward additional avenues of a common cause between hearing loss and dementia  are thought to contribute toward the association , these fIdentification of research priorities given the transdisciplinary scope of study on hearing and dementia will aid in achieving foundational dementia research goals: to advance our identification of subgroups of adults who may present greater risk for cognitive decline/dementia or suggest novel options for intervention or prevention. Numerous pressing research questions and additional perspectives on the importance of these questions prevail . Here weGiven the varied temporal contributions of each proposed mechanistic pathway, determination of which pathway(s) serve as the primary driver behind the association is vital. This determination may allow for improved study design and planning and well as more informed clinical intervention to delay or prevent the onset of cognitive symptoms and delay the progression along or alter the trajectory of the clinical course of dementia. With the current insufficient evidence to declare hearing loss has an independent effect on cognitive impairment for older adults, how we should intervene on hearing loss, when to do so, and if such interventions are effective in decreasing or delaying dementia risk will all largely depend on the underlying mechanism. We know the presentation of dementia symptomatology is heterogeneous across individuals even with the same underlying pathology. We have yet to determine by what manner hearing loss may influence a potential buffer which delays/prevents the presentation of symptoms in some individuals yet fails do so in others, leading to earlier symptomatology.If the association between hearing loss and dementia is only due to a common cause, the potential for directly delaying or preventing changes in the presentation of dementia symptoms or pathology through hearing would be extremely limited as the underlying cause would remain untreated. The research intervention focus would ultimately turn toward the underlying common confounder, which could then have downstream effects for hearing and cognition. However, the use of hearing management such as hearing aids may support cognition through indirect pathways like improving social engagement and communication yet decreasing cognitive load and strain on central auditory function through improvement of peripheral auditory input, directly preventing dementia would remain elusive.A direct effect of hearing loss on cognitive function is inferred with the sensory-deprivation and information degradation hypotheses. A long-term versus short term-effect is implied depending on the proposed pathway, yet both advocate that hearing loss, and notably untreated hearing loss, leads to downstream consequences for cognitive resources with important implications for approaches to intervention. The sensory deprivation hypothesis posits structural and functional changes in the brain due to lack of auditory stimulation. Therefore, preemptive identification of hearing loss and early adoption of treatment strategies which delay or prevent deafferentation or atrophy within the auditory or sensory regions of the brain are essential to prevent lasting structural damage. Importantly, auditory rehabilitation to prevent structural and functional changes in the brain through sensory deprivation may even have benefit at later stages of hearing loss by delaying additional neural reorganization or atrophy. For comparison, the information degradation hypothesis strongly supports hearing intervention at any time in the disease process. With restoration of the integrity of auditory stimuli via rehabilitation or hearing management, the cognitive demands and utilized cognitive resources for speech and environmental awareness would in theory be reduced, allowing for cognitive resources to again be allocated to overall cognitive processing and compensation.It is imperative we determine how to disentangle CAD and cognitive decline if we are to consider its use in targeting prevention efforts or early identification of subgroups at greater risk for cognitive decline. How to differentiate between changes in cognitive processing and CAD, the temporality between each processing condition, and whether CAD may serve as an early marker for specific subtypes of dementia remains a challenging barrier for characterizing the link between hearing loss and dementia. While the majority of research to date has focused on the association between hearing loss and Alzheimer’s disease since the most common form of dementia and pathology observed, distinctions in association with other dementia pathologies is paramount. The dependence and entanglement of both forms of hearing on higher-level cognitive functioning stirs question of how to interpret the role of each process along the auditory pathway. If CAD may serve as an early marker of dementia remains to be determined.As stated, it is likely multiple mechanistic pathways are involved in the hearing-dementia association. Determining if one pathway serves as the primary driver, or if the pathway is unique to the individual may provide an opportunity for a person-centered approach to dementia prevention and intervention. Furthermore, while not mutually exclusive, determining the role of central vs. peripheral hearing in the hearing-dementia association will further inform research and clinical use of hearing and prevention or as an early marker of dementia.A goal of any neurocognitive test battery is to accurately measure cognitive function for all individuals. Yet the validity of cognitive assessments inherently depends on an individual’s auditory or visual ability to access test materials. This interdependence has led some to question whether there is a bias or confounding introduced by a sensory impairment during cognitive testing for older adults . An inveWhile exclusion of those with severe sensory loss from testing might ensure completion of evaluations, this exclusion limits our understanding of the role of sensory loss in cognition. One way to assess cognitive function among those with hearing loss may be to utilize cognitive test batteries that are administered via visual modality rather than auditory. However, this strategy does not fully address issues that arise among those with dual sensory impairment .An alternative approach to address sensory loss when administering cognitive assessments is to consider accommodations for the sensory loss . If an iRecent decades have seen an accumulation of evidence for the impact of treating hearing loss on cognitive decline or dementia. Our observational studies have provided foundational and pivotal insights into the hearing-dementia association, however, evidence of causality for decreased or delayed cognitive decline due to hearing aid use is more challenging. From a neurocognitive perspective on this investigation, challenges include selection effects of older adults into studies. Individuals who pursue and obtain a hearing aid are generally a select group of adults— often with higher education, higher income, and greater health seeking behaviors— all of which are considered protective factors for cognitive decline .Many barriers to obtaining hearing aids still exist within the United States and must be considered within the context of existing research on the use of hearing aids as dementia prevention or intervention. Hearing aid and aural rehabilitation services are not covered under Medicare or many private insurances, placing the cost of the device and services (often $1000 or more) on the individual and family. Further, an audiologic evaluation and aural rehabilitation appointments are not currently available through direct-access to patients under some American insurances, but require referral from a primary care physician or specialist . This adWithout understanding the mechanism(s) behind the hearing-dementia association, it is challenging to determine how and when is best to intervene on cognitive decline and dementia. Evidence for treatment of hearing loss throughout the dementia continuum is growing, yet many questions remain. Evidence of efficacy, effectiveness and cost efficiency will aid in determining the best aural rehabilitation choices for prevention — all areas with extensive gaps in evidence for hearing loss and dementia.In addition to potentially serving as a dementia prevention strategy, hearing aids may present opportunity for intervention for neuropsychiatric symptoms (NPS) at all stages of dementia and negative health outcomes associated with NPS . BreakdoAdditional work is needed to determine how best to provide auditory rehabilitation for adults with cognitive impairment. A recent study  suggestsWhile hearing aids serve as the most prominent means of hearing intervention, other means of aural rehabilitation are available such as personal amplifiers, general assistive listening devices, or auditory training strategies. Research is limited on the use of these alternative strategies for treatment of hearing loss along the dementia continuum, yet determination of a variety of accessible alternative strategies is fundamental for providing communication ability and social engagement for older adults. Hearing aids may not be feasible for some older adults  and likely do not meet the listening needs of many adults when used as the only form of rehabilitation. As mentioned, adaptation to increased auditory stimuli requires extensive cortical adjustment which may overwhelm some individuals without proper counseling and consideration. Non-technology driven alternative strategies   require Importantly, the use of hearing aids has a primary role in management of peripheral hearing loss, contributing to the focused effort of public health research on peripheral rather than central hearing ability and the association with cognitive decline/dementia. If the pathway linking hearing to cognition is related (directly or in part) due to central auditory processing and ability, the use of hearing aids as a prevention and intervention option for dementia will have minimal effect given the state of current technology and auditory processing treatments. While hearing aid use may not delay the progression of dementia pathology if the association is due to a common cause, as stated above the use of hearing aids may still indirectly support intervention of progression of the clinical presentation of dementia symptoms through indirect pathways such as decreased cognitive load and improved social stimulation. Future advances in hearing aid technology which may better address cognitive and central auditory demands may provide even greater benefit. Currently, evidence for the role of central auditory processing and central hearing disorders for early identification of dementia will have heightened importance and emphasize the need for consideration of greater use in neuropsychological and medical evaluations.if hearing or vision may serve as an early marker of dementia- a point which has yet to be determined and has received minimal study  driving the association between hearing and dementia, consideration of sensory loss during cognitive testing or in care strategies for those with dementia or dementia prevention, and targeted future directions of research can have a significant impact on prevention and intervention strategies for older adults. The interdependent and synergistic processes of hearing and cognition require careful approach for research and clinical care. The current limitations in dementia treatment necessitate innovative approaches for dementia intervention. Identification of additional early markers of dementia, a potential role of central auditory function with continued research may aid in this process, as well as inform optimal strategies for hearing management itself. Considering the presence of other conditions, like hearing loss, and optimizing our strategies to evaluate and treat hearing loss could diminish the risk of adverse outcomes and enhance health and quality of life for older adults.DP was responsible for the initial drafting, editing, and formatting. EO, NR, FL, and JD contributed to content and editing. All authors contributed to the article and approved the submitted version.NR reports being a scientific advisory board member of Shoebox Inc and Neosensory. FL reports being a consultant to Frequency Therapeutics, speaker honoraria from Caption Call, and being the director of a public health research center funded in part by a philanthropic gift from Cochlear Ltd to the Johns Hopkins Bloomberg School of Public Health. 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.


Although lower extremity arterial disease (LEAD) is most often multisegmental, the predominant disease location and risk factors differ between patients. Ankle-brachial index (ABI), toe-brachial index (TBI), and toe pressure (TP) are predictive of outcome in LEAD patients. Previously, we reported a classification method defining the most diseased arterial segment (MDAS); crural (CR), femoropopliteal (FP), or aortoiliac (AOI). Current study aimed to analyze the associations between MDAS, peripheral pressure measurements and cardiovascular mortality.We reviewed retrospectively 729 consecutive LEAD patients (Rutherford 2–6) who underwent digital subtraction angiography between January, 2009 to August, 2011 and had standardized peripheral pressure measurements.In Cox Regression analyses, cardiovascular mortality was associated with MDAS and non-invasive pressure indices as follows; MDAS AOI, TP <30 mmHg ; MDAS FP, TP <30 mmHg , TBI <0.25 , ABI <0.25  and ≥1.30 , and MDAS CR, TP <30 mmHg , TBI <0.25 , and ABI <0.25 .Symptomatic LEAD appears to be multisegmental with severe infrapopliteal involvement. Because of this, TP and TBI are strongly predictive of cardiovascular mortality and they should be routinely measured despite the predominant disease location or clinical presentation. Lower-extremity arterial disease (LEAD), both symptomatic and asymptomatic, is associated with elevated risk for cardiovascular and all-cause mortality . ChronicCurrent guidelines recommend ankle-brachial index (ABI), the highest systolic ankle pressure divided by the highest systolic brachial pressure, as the first line test for screening and diagnosis of LEAD . VasculaExtensive atherosclerosis in different arterial segments, aortoiliac (AOI), femoropopliteal (FP), and crural (CR), has been noted to associate with distinctive risk factors and disease etiology –15. MajoPreviously in one study, a decline in ABI has been interpreted as disease progression in large-vessels when a reduction in TBI has been associated with progression in small vessel disease . As atheThis is a retrospective patient cohort study. Irrespective of earlier vascular history or procedures, all patients (887) at the Turku University Hospital vascular unit who underwent digital subtraction angiography (DSA) from January 1, 2009 to August 31, 2011, were recruited to the study. Of these (Rutherford 2–6), 729 patients (82.2%) who both underwent DSA and had standardized peripheral pressure measurement in vascular laboratory were included for the final analyses. Patients were subjected to DSA for either diagnostic or intention-to-treat reasons. Within the recruitment, DSA was the gold standard imaging modality to visualize atherosclerotic changes in lower limb arteries at our vascular department. The limb with the lowest average TP was selected to the study. If repetitive DSAs were performed over the study period, only the first DSA was included in the study.The demographic patient data was retrospectively collected from the hospital electronic operations database. The date of DSA served as the index date for the survival. The comorbidities registered according to the International Statistical Classification of Diseases and Related Health Problems classification system (ICD-10) were collected as follows; coronary artery disease (CAD), hypertension (HT), end stage renal disease (ESRD), dyslipidemia, and atrial fibrillation (AF). diabetes (DM), cerebrovascular disease (CVD), sleep apnea, and chronic obstructive pulmonary disease (COPD).The baseline medication , severity of ischemia (Rutherford classification ) and smoHemodynamic measurements were conducted with Nicolet VasoGuard  photoplethysmography in Turku University Hospital Vascular Laboratory. All assessments were standardized and obtained in a systematic manner; patients were in supine position with the limb at the level of the heart. To obtain limb pressures, pneumatics cuffs were inflated until the flow signal ceased and then slowly deflated until the pulsatile signal reappeared. Overall, the lowest value of the pressure measurement was registered.To assess ABI, the systolic ankle pressure was divided by the higher systolic brachial pressure. TP was assessed from the great toe and in case it was missing, from the nearest available toe. To reduce the effect of local vasoconstriction, the patients’ feet were pre-warmed before the measurements. TBI was measured by dividing the toe’s systolic pressure by the brachial systolic pressure.According to the TransAtlantic Inter-Society Consensus II (TASC II) classification on CLTI, peripheral pressure measurements were then categorized . For TP,First, all DSA images were analyzed to assess MDAS. This process of the determination of MDAS was initially introduced by Jalkanen et al. . All theAOI and FP segments were classified according to the TASC II criteria. To assess the state of atherosclerosis in each segment, AOI and FP segments were coded as follows; no disease:0, TASC II A: 1; TASC II B: 2; TASC II C: 3 and TASC II D: 4. In CR segment, each of the three CR vessels were analyzed and coded individually as follows: No detectable or minor disease: 0; Total occlusion less than 5 cm: 1; Total occlusion less than 15 cm: 3; Total occlusion more than 15 cm: 4. Finally, the Crural Index (CIx) was then assessed by a sum of the these three CR vessels: if the sum was 0 the CIx was 0; if the sum was 1–3 the CIx was I (1); if the sum was 4–6 the CIx was II (2); if the sum was 7–9 the CIx was III (3) and if the sum was 10–12, the CIx was IV (4).Based on TASC II and CIx classifications, each segment was scored from 0–4. The arterial segment reaching the highest score was defined as MDAS. According to this, patients were assigned into either 1) MDAS AOI, 2) MDAS FP, or 3) MDAS CR group. For instance, CIx III (3) ruled out proximal lesions of 0–2 and therefore, the predominant disease location was CR and patients were analyzed in the group MDAS CR. As an exception, the most proximal location was chosen if the highest grade was equal in two or even three locations.The study protocol was approved by the local ethical committee of the Hospital District of Southwest Finland with a decision ID TK-53-1266-15 and due to the retrospective nature of the present study, no informed consent was required. This study conforms to the ethical guidelines of the 1975 Declaration of Helsinki.Statistical analyses were performed using the IBM SPSS ® version 26 statistics program. Shapiro-Wilk test was used to test the normality. Continuous variables were expressed as mean ± standard deviation (SD) and Kruskal-Wallis test was used for comparisons. Categorical variables were expressed as frequency and percentage and comparisons were performed by Chi-square test. A Cox regression analysis was performed to assess the predictive value of factors affecting survival. The following confounding variables were added to the model; age, male sex, CAD, hypertension, DM, smoking, and ESRD. In Multivariate Cox regression analyses, cardiovascular cause of death was considered as the outcome. The highest group was selected as reference for categorical pressures and indices except ABI, where ABI 0.90–1.29 were selected as reference category. Survival curves were estimated for each group using the Kaplan-Meier method and compared statistically using the log-rank statistics. To estimate the validity of the findings, the calculation of sample size was based on the cardiovascular mortality at 3-years with the assumption of the alpha-level of 0.05. To achieve a power of 80% (beta-error 0.2) with TP <30 mmHg, sample size calculation resulted in 69 patients. Correspondingly, the calculated sample size was 84 for TBI <0.25 and 75 for ABI <0.25. All authors had full access to all the data in the study. The corresponding author takes responsibility for the integrity of the data analyses. Data cannot be shared publicly because of patient identification. Data are available from the corresponding author for researchers who meet the criteria for access to confidential data.Demographic characteristics overall and according to MDAS are presented in Number of patients according to TP, TBI and ABI and MDAS are presented in p<0.001). For MDAS AOI, 1-, 2- and 3-years survival was 96.0%, 96.0%, and 89.1%, respectively. For MDAS FP, the corresponding proportions were 93.4%, 88.2%, and 84.9%, and for MDAS CR, 81.9%, 71.3%, and 63.1%, respectively.Altogether, 28.8% (N = 210) patients died due to cardiovascular causes during the follow up; 12.4% in MDAS AOI (N = 26), 40.0% in MDAS FP (N = 84), and 47.6% in MDAS CR (N = 100)  were in MDAS CR compared to other MDAS groups. Interestingly, severe concomitant CR involvement was not a rarity in MDAS FP (CIx III-IV 35.1) and MDAS AOI groups  and similarly to MDAS CR, an association between TBI, TP and cardiovascular mortality was observed. As digital arteries are often spared from arterial wall stiffening, TP and TBI seem to offer the most sensitive risk estimation in multisegmental LEAD. Based on these observations, the extent of CR atherosclerosis seems to correlate with the TP and TBI in a linear fashion.The assessment of peripheral pressures is feasible and straightforward to estimate survival and they can be applied to everyday practice compared to invasive methods. Our present observations support the use of all three measurements, ABI, TP and TBI as they are all provide valuable risk estimation. In symptomatic LEAD, diseased CR region and medial calcification are commonly present, which may explain why TP and TBI have strong association to mortality. When acknowledging the multisegmental nature, each of these non-invasive pressure measurements should be considered when evaluating the risk for cardiovascular mortality. Especially in patients with near normal ABIs, TBI and TP may be particularly useful tools for risk estimation.The cohort consisted of LEAD patients (Rutherford 2–6) with intension-to-treat (invasive imaging) and therefore, the generalizability of our results to the whole population remains uncertain. Demographic information was obtained from patients’ medical records, thus there is a heavy reliance on accurate recording of the comorbidities. Strengths of this study are the long follow-up periods and an adequately sized study cohort. ABI, TP, and TBI were registered in a vascular laboratory setting by trained nurses. Unfortunately, in MDAS AOI, unbalanced ABI categories limited the risk evaluation.As symptomatic LEAD appears to be multisegmental with severe infrapopliteal involvement, our present observations support the use of all three peripheral pressure measurements, ABI, TBI and TP in risk estimation. Despite the predominant disease location or clinical phenotype, TP and TBI have a strong association to cardiovascular mortality.


It is generally believed that ultrasound cannot be heard. However, ultrasound is audible when it is presented through bone conduction. Bone-conducted ultrasound (BCU) has unique characteristics; the most interesting is its perception in patients with profound deafness. Some patients can perceive it and discriminate speech-modulated BCU. Previous reports have suggested that BCU can be used for a hearing aid or tinnitus sound therapy. In this review, the perception of BCU at both the peripheral and central levels was investigated based on previous studies, although some of them remain controversial. We also investigated the clinical use of BCU. To develop hearing aids utilizing BCU, the encoding of speech signals into BCU has to be established. The outcomes of the reported speech modulations were evaluated. Furthermore, the suppression of tinnitus by BCU was reviewed, and the feasibility of the application of BCU to tinnitus treatment was investigated. The audible frequency range of the human ear is between 16 Hz and 24 kHz ,4. PreviAccording to previous reports, the pitch of BCU resembles that of ACAS at frequencies of 8–16 kHz, independent of its own frequencies ,4,6. TheFor audible sound, the presentation of an acoustic stimulus can disturb the perception of other sounds (masking), and the amount of masking grows as the difference between the frequencies of the two sounds reduces. The masking of ACAS by BCU can be used to establish its perception mechanism. In our previous study, ACAS at frequencies below 8 kHz was not masked by BCU, which suggested that ultrasonic perception was not significantly associated with the perception of ACAS at frequencies of ≤8 kHz . In contIf the peripheral perception organ of BCU is located in the cochlea, ultrasonic perception may be possible to be completely masked by ACAS. In previous studies, ultrasonic perception was barely masked by ACAS ,16. HoweIn our hypothesis of the peripheral perception mechanism, the function of OHCs does not contribute to ultrasonic perception. Inner hair cell (IHC) activity induced by ultrasound plays an important role in ultrasonic perception, even without the presence of modulation, and it does not depend on the enhancement of BCU by OHCs in the basal turn of the cochlea. Regarding the thresholds of BCU in patients with hearing impairment, no patients with an estimated total loss of the IHC system in the cochlear basal turn could hear BCU . A signiIn previous studies on ultrasonic perception at the central level, neural activation was observed with magnetoencephalography and positron emission tomography in the auditory cortex but not in the somatosensory cortex ,10. ThesOne of the clinical applications of ultrasonic perception is hearing aids for profound deafness. Some characteristics of ultrasonic perception resemble those of the perception provided with a cochlear implant rather than those of ACAS perception. The most pertinent difference between BCU and cochlear implants is the spectral resolution. BCU can stimulate one broad cochlear region in the basal turn, which can be considered a single-channel hearing device, whereas cochlear implants have multiple channels ,27,28. SIn previous studies, speech-modulated BCU facilitated good speech recognition scores for participants with normal hearing ,32,33. TChanges in voice pitch contribute to communication. During conversation, speech sounds convey both linguistic and non-linguistic information, such as attitudes and emotions. Prosody is important for the conveyance of information, such as questions or affirmations, through speech and the expression of emotions. In a previous behavioral study, prosodic information for speech-modulated BCU could also be distinguished during normal hearing . FurtherIf demodulation works in the perception of speech modulated BCU, good speech recognition without any training by participants with normal hearing can be explained without difficulty. BCU modulated by speech signals may be demodulated into original signals, and, consequently, most participants would be able to recognize them. In contrast, this also means that hearing-impaired patients, especially profoundly deaf patients, cannot recognize any speech signals because demodulated audible sound cannot be recognized because of their hearing disorder. In contrast, Lenhart et al. reported the discrimination of speech-modulated BCU in patients with severe hearing loss . Hosoi oOur previous study investigated the intelligibility of speech-modulated BCU using a numeral word list under masking conditions . In the Tinnitus is a common audiological disease, and the prevalence of continuous subjective tinnitus among adults ranges from 5.1% to 42.7% . It negaTinnitus is temporarily masked by presenting a sound, and it is continuously reduced or disappears during the few seconds or minutes after the offset of the masker presentation. This continuous reduction or disappearance of tinnitus is referred to as residual inhibition (RI). RI has been regarded as a clinical index that reflects the degree of tinnitus inhibition . GoldsteSound therapy is regularly administered during daily life. When a sound generation device is used for sound therapy, a generated sound is presented with an earphone for a defined therapy session. During the session, hearing can be disturbed by the generated sound. However, if BCU is used as the presented sound, it rarely affects hearing within the frequency range involved in daily conversation. In addition, ultrasound is delivered via BC, and the insertion of an earphone is not required. Thus, sound therapy utilizing BCU may minimize its influence on daily life and provide good benefits. Further studies on tinnitus therapy using BCU are required.BCU is perceived in the basal turn of the cochlea. However, its perception mechanism is different from that of ACAS. The intelligibility for the speech-modulated BCU is comparable to that for the original speech signal in normal-hearing individuals due to the contribution of demodulation. Unfortunately, the lack of the contribution of demodulation to speech perception has to be taken into consideration in hearing impairment patients. The performance of the reported speech-modulated BCU in speech recognition is limited in patients with profound deafness, and further innovation may be required for clinical use. Regarding the application to tinnitus treatment, BCU devices have unique advantages. Unfortunately, the knowledge of BCU in this field has not been sufficient, and further study is required for its establishment.


ABSTRACT IMPACT: Findings from this study will better characterize the role of hearing loss in falls risk among patients with vestibulopathy and identify groups that are most at risk for falls. OBJECTIVES/GOALS: Vestibular dysfunction and hearing loss are independent risk factors for experiencing falls. The purpose of this study is to determine the extent, if any, to which hearing loss contributes to falls in patients with concomitant vestibular dysfunction presenting to a specialty vestibular clinic. METHODS/STUDY POPULATION: A retrospective chart review of patients ≥18 years who underwent vestibular evaluation at our institution from June 1, 2015 to October 7, 2020 will be conducted. Patients who underwent vestibular evaluation also received audiologic evaluation and degree of hearing loss will be characterized by the 4-frequency pure-tone average  of the better hearing ear. Falls status will be determined by the response to the following question administered at clinic-check in, ‘Have you fallen in the last 90 days?’ Demographics, comorbidities, and falls-associated medications will also be collected. RESULTS/ANTICIPATED RESULTS: A total of 3,265 unique patients who underwent vestibular evaluation in the study time period were identified. Patients will be categorized into discrete groups  based on laboratory results. Regression models will be developed to evaluate the potential association between degree of hearing loss and falls in patients with different types of vestibular dysfunction, while adjusting for demographics, comorbidities, and falls-associated medications. DISCUSSION/SIGNIFICANCE OF FINDINGS: Findings from this study will better characterize the role of hearing loss in falls risk among patients with vestibulopathy and identify groups that are most at risk for falls. This study may potentially indicate the importance of hearing evaluation in the work-up of patients with vestibulopathy.


It is largely assumed that the teleost retina shows continuous and active proliferative and neurogenic activity throughout life. However, when delving into the teleost literature, one finds that assumptions about a highly active and continuous proliferation in the adult retina are based on studies in which proliferation was not quantified in a comparative way at the different life stages or was mainly studied in juveniles/young adults. Here, we performed a systematic and comparative study of the constitutive proliferative activity of the retina from early developing (2 days post-fertilisation) to aged (up to 3–4 years post-fertilisation) zebrafish. The mitotic activity and cell cycle progression were analysed by using immunofluorescence against pH3 and PCNA, respectively. We observed a decline in the cell proliferation in the retina with ageing despite the occurrence of a wave of secondary proliferation during sexual maturation. During this wave of secondary proliferation, the distribution of proliferating and mitotic cells changes from the inner to the outer nuclear layer in the central retina. Importantly, in aged zebrafish, there is a virtual disappearance of mitotic activity. Our results showing a decline in the proliferative activity of the zebrafish retina with ageing are of crucial importance since it is generally assumed that the fish retina has continuous proliferative activity throughout life. Neurogenesis is the process by which neural progenitor cells give rise to mature neurons and glial cells. Early in development, the central nervous system (CNS) is formed from a highly active neurogenic neuroepithelium. As development progresses, proliferative and neurogenic activities are gradually lost in most CNS regions, and, in postnatal life, neurogenic activity is restricted to specific regions called neurogenic niches ,2. MoreoPetromyzon marinus, and the catshark, Scyliorhinus canicula, revealed the loss of proliferative activity in the retina of adult individuals of these ancient vertebrate groups ) to young adult (6–8 months post-fertilisation [mpf]) stages revealed a sharp decline in the rate of retinal growth between 3 and 4 days post-fertilisation (dpf) and a decline in the rate of cell addition between embryos and young adults ). Our results show that there is a progressive loss of proliferative activity in the retina throughout life in zebrafish despite the occurrence of a wave of secondary proliferation during sexual maturation. Importantly, mitotic activity is virtually absent in the retina of old animals.The zebrafish retina exhibits the typical morphology and structure of the vertebrate retina, with a CMZ located at the retinal margin containing different types of progenitor cells A and a hIn this study, we analysed zebrafish of different developmental/life stages: 2, 4, and 7 dpf, 1.5, 2.5, 3, 8.5, and 18–20 mpf and 3–4 ypf. The 2 to 7 dpf period coincides with early zebrafish development B. From 1In the 2 dpf animals, the retina did not show the typical layered organisation of a mature vertebrate retina, and it is mainly formed by neuroepithelial cells C. As canTo compare the number of cells progressing through the cell cycle and cells undergoing mitosis in the zebrafish retina at different developmental/life stages, we used double immunofluorescence to detect the expression of PCNA, which is present in proliferating cells during every phase of the cell cycle, peaking from G1 to S and decreasing at G2/M, and pH3, a marker of M-phase cells . Our comMitotic (pH3+) cells were mainly observed in the CMZ, and, in this region, most of them were observed in the apical surface, i.e., near the ventricle A–D. HoweIn the whole retina, the number of pH3+ cells significantly and progressively decreased during early development from 2 to 7 dpf . InteresVery similar trends in temporal expression patterns were observed when looking separately at the number of pH3+ cells per section in the CMZ  and centOur results indicate that proliferative activity decreases with age in both the CMZ and central region of the zebrafish retina despite the occurrence of a secondary wave of proliferation during sexual maturation . Importantly, mitotic activity is virtually absent in aged specimens.We separately quantified the numbers of pH3+ and PCNA+ cells in the cell layers of the central retina  at the different developmental and life stages ; File S2As indicated in the Introduction, it is largely assumed that the retina of fishes shows continuous and active proliferation and neurogenesis throughout life. This assumption is based on previous work in teleost models in which the presence of proliferating cells was only studied in juveniles or young adults, in animals in which the precise age was not defined or known by the authors of the study, or without performing quantitative comparisons between all life stages or ages see . This feHere, we obtained quantitative data comparing the cell cycle progression (PCNA+ cells/section) and mitotic activity (pH3+ cells/section) in both the CMZ and the central zebrafish retina at different ages and covering all major life stages. Our results show that there is a drastic decline in proliferative activity from 2 to 7 dpf, a continuous reduction in the number of proliferating cells in sexually maturing and old animals, and that cells undergoing mitosis are virtually absent in old animals. This is in good agreement with previous reports of a drastic decrease in cell proliferation in early larvae  and witUnlike previous reports on the proliferation in the zebrafish retina, our systematic analysis allowed unveiling the occurrence of a secondary wave of proliferation during sexual maturation  affecting both the CMZ and the central retina. Only a study by Bernardos et al.  providedBy looking at the distribution of the proliferating/mitotic cells in the cell layers of the central retina at different ages, we observed that, in early developing 4 dpf specimens, the numbers of pH3+ and PCNA+ cells were higher in the INL, whereas, in older animals, they were more abundant in the ONL. Previous studies have shown that the progenitor cells of the central retina (Müller glia) in juvenile/adult goldfish ,48,49 ann = 16), 4 dpf (n = 17), 7 dpf (n = 11), 1.5 mpf (n = 7), 2.5 mpf (n = 10), 3 mpf (n = 8), 8.5 mpf (n = 5), 18–20 mpf (n = 9), and 3–4 ypf (n = 7) zebrafish (Danio rerio) specimens were used in this study. Zebrafish were kept in aquaria under standard conditions of temperature (28 °C), light cycle (14 h of light and 10 h of darkness), and pH (7.0) until use for experimental procedures. All juvenile/adult fish were kept at a density of 3 fish/litre, and food supply was under strict standardised control to avoid differences in animal size in each of the experimental groups [2 dpf , euthanised, and fixed by immersion in 4% paraformaldehyde in 0.1 M phosphate-buffered saline pH 7.4 (PBS) for 2 h (from 2 to 7 dpf) and 1 day (from 1.5 mpf to 3–4 ypf) at 4 °C. After fixation, the lens was removed from the eye in specimens from 1.5 mpf onwards. Eyes were dissected out from the rest of the body in specimens from 8.5 mpf onwards. After rinsing in PBS, the animals or eyes were cryoprotected with 30 % sucrose in PBS, embedded in Neg-50TM , and frozen with liquid nitrogen-cooled isopentane. Transverse sections (18 μm thick) were obtained on a cryostat and mounted on Superfrost Plus slides .Some sections from 2 dpf and 1.5 mpf specimens were stained with haematoxylin–eosin following standard protocols. Briefly, cryostat sections were dried at room temperature (RT), rinsed in 0.05 M Tris-buffered (pH 7.4) saline (TBS) for 10 min, and stained with haematoxylin solution for 10 min. Sections were subsequently rinsed in tap water until removal of the excess of haematoxylin, in distilled water for 10 min, and then stained with eosin for 2 min. Finally, the sections were dehydrated and mounted in DPX mounting medium .® 4–88 .Sections were first pre-treated with 0.01 M citrate buffer pH 6.0 for 30 min at 90 °C for heat-induced epitope retrieval, allowed to cool for 20 min at RT, and rinsed in TBS for 5 min. Then, sections were incubated overnight at RT with a combination of two primary antibodies: a mouse monoclonal anti-PCNA  and a rabbit polyclonal anti-pH3) . Sections were rinsed 3 times in TBS for 10 min each and incubated for 1 h at RT with a combination of fluorescent dye-labelled secondary antibodies: a Cy3-conjugated goat anti-rabbit  and a FITC-conjugated goat anti-mouse . All antibody dilutions were made in TBS containing 15% normal goat serum (Millipore), 0.2% Triton X-100 (Sigma-Aldrich), and 2% BSA (Sigma-Aldrich). Sections were then rinsed 3 times in TBS for 10 min each and in distilled water for 30 min, allowed to dry for 30 min at 37 °C, and mounted in MOWIOLOryzias latipes [Haplochromis burtoni [Onchorynchus mykiss [Tinca tinca [Carassius auratus [Salmo trutta fario [Danio rerio [Scyliorhinus canicula [Petromyzon marinus [Carassius auratus [Scyliorhinus canicula [Danio rerio [Anti-PCNA antibodies (including the one used in this study) have been traditionally used to label proliferating cells in the retina of different fish (including zebrafish):  latipes ; Haploch burtoni ,58; Onchs mykiss ; Tinca tca tinca ,61,62; C auratus ,61; Salmta fario ; Danio rio rerio ; Scyliorcanicula ,67,68,69 marinus . Anti-pH auratus ; Scyliorcanicula ,65,70; aio rerio ,72,73.z-axis. Collapsed images of the whole retinal sections (18 µm) were obtained with the LITE software . For figure preparation, contrast and brightness of the images were minimally adjusted using Adobe Photoshop CS4 .Brightfield images of haematoxylin–eosin-stained sections were taken with an Olympus BX51 microscope equipped with an Olympus DP71 camera. Images of fluorescent labelled sections were taken with a Leica TCS-SP2 confocal microscope with a combination of blue and green excitation lasers. Confocal optical sections were taken at steps of 1 μm along the We quantified the number of mitotic cells (pH3+) in the whole retina  and cells progressing through the cell cycle (PCNA+) in the central retina. As indicated above, the number of PCNA+ cells was not quantified in the CMZ because, at some stages (mainly 2 dpf), the high number of positive cells impeded to clearly differentiate between cells individually. In any case, the number of PCNA+ cells/section in the CMZ of adult zebrafish (6 to 48 mpf) was previously examined by Van Houcke et al. .The numbers of pH3+ and PCNA+ cells were manually counted under a fluorescence microscope in one out of each two consecutive retinal sections (thickness of 18 μm). The limit between the CMZ and the central retina was established based on the expression pattern of PCNA, which is mainly found in the most peripheral region of the retina. In 2 dpf specimens, we did not separate pH3+ cell quantifications of the CMZ and central retina because, at this developmental stage, PCNA was highly expressed throughout the entire retina, which impeded to establish a clear limit between both regions. We calculated the mean number of cells per section for each retina. Then, we calculated the mean number of cells per retinal section for each animal based on the values for the two retinas and used that value for statistical analyses . We also quantified the differential distribution of pH3+ and PCNA+ cells in the different cell layers of the central retina from 4 dpf onwards: the GCL, the INL, and the ONL.Statistical analyses were performed with Prism 8 . Normality of the data was determined with the Kolmogorov–Smirnov test. An ordinary one-way ANOVA followed by a Tukey’s multiple comparison test was used to determine statistically significant differences in normally distributed data. A Kruskal–Wallis test, followed by a Dunn’s multiple comparison test, was used to determine statistically significant differences in non-normally distributed data.Our results reveal a decline in constitutive proliferative activity in the zebrafish retina with ageing. Importantly, mitotic activity is virtually absent in aged animals. Statements regarding the continuous and high proliferative activity in the fish (teleost) retina throughout life should be nuanced.Interestingly, our systematic study also detected the presence of a secondary wave of cell proliferation during sexual maturation in the zebrafish retina. A possible relationship to the generation of the photoreceptors needed for sexual/adult behaviours is suggested. Future work should try to decipher the origin and destiny of these progenitor cells and their relationship to zebrafish behaviour.


The COVID-19 outbreak caused almost all countries to declare public health emergencies. The government, medical institutions and even civil societies are taking up measures to deal with the pandemic . In thatChina has a relatively positive attitude towards remote court hearings compared to other countries. The pandemic has accelerated the development and application of remote court hearing in China. This is evident as cases handled through electronic litigation have increased considerably ,5. HowevChina’s remote court hearing system can give researchers an insight into this system and be applied in their own countries. As it currently seems, remote court hearing is here to stay, even after the pandemic. As such, we need to develop strategies and techniques to improve remote court hearing by asking ‘Is it necessary to develop remote court hearing, and does it fit in with the public health emergencies? How do we evaluate the impact of remote court hearing, and how do we standardise this system to enhance the ability of judiciary to deal with public health emergencies and promote the modernisation of judicature?’I analyzed the judgement documents from China Judgements Online. The lasIt can be see that the COVID-19 outbreak has had a significant impact on the application of remote court hearings. The judiciary regards remote court hearing as an important measure to deal with the current outbreak.As shown in Based on From the 7221 cases that demonstrably use remote court hearings, 5525 cases of remote court hearings were for first instance procedures; 1640 cases were for second instance procedures; and 56 cases were for retrial procedures. The practice of remote court hearing in China reflects the demand to innovate during public health emergencies. In 2020, the number of cases, geographical scope and procedural scope of remote court hearings all showed a rapid growth trend which allowed the process of litigation to continue despite the public health emergency. However, the existing practices of remote court hearing in China present a great variety of forms, which means that remote court hearings urgently need theoretical care and normative guidance.Regarding the scope of procedures, both the summary procedures and small claims procedures, as well as ordinary procedures, can be tried through remote court hearings. In addition, not only cases of first instance procedures can be conducted through remote court hearings, but also cases of second instance procedures or retrial procedures are under the category of remote court hearings. In a geographical scope, remote court hearings are not only limited to the pilot courts. There are variations on how remote court hearings are conducted. Some courts rely on the platforms that they themselves have developed . Others use third-party platforms such as QQ  and WeChat . Some courts adopt video calls , and some use voice calls . Others start with the request or consent of only one party , while some commence their hearings with the requests or consent of both parties .Court hearings are concentrated in the fields of litigation, legal communication and realisation of one’s rights. Whether its construction is normative or not is directly related to the judicial power and the rights of the parties in the case. Even if remote court hearings are necessitated by public health emergencies, justice, parties’ rights and other factors of litigation must be carefully considered and observed. Therefore, it is necessary to assess the impact of remote court hearings and develop appropriate responses and strategies.Remote court hearing, also called online court hearing, refers to the online process of hearing proceedings without the physical presence of the subjects of litigation using computer and internet as a medium to transmit texts, voices, images and related information. Compared with the traditional way of court hearing, remote court hearing is technology dependent, relies on network stability, flexible and paperless. The characteristics of remote court hearing can also improve the court’s ability to deal with public health emergencies.Remote court hearings help reduce the risk of infection and improve their court appearance rate. In an age centred on information and internet technology, online communication slowly removes barriers between people, which makes us connect more easily to others. Remote court hearings enable both parties to communicate freely, and makes hearings more convenient to all parties involved. As long as the litigants have the equipment and network, they can enter the court hearing in a non-face-to-face manner instead of attending hearings in person. Remote court hearings reduce contact between people and uses technology to transmit communication information and complete online statements, defences, evidence presenting, cross-examinations and inquiries. In the application of remote court hearing, litigation documents and evidence materials are presented, transmitted, reviewed and kept on file electronically. This helps to further reduce contact transmission.In summary, remote court hearings are borne from a need to continue litigation despite public health emergencies. As scholars have said, modern justice must be effectively accessible to all, not just theoretically . Even duAristotle says that the precision of things needs to be found in the nature of the subject . The natAccording to the theory of litigation, court hearing is an activity of directness, orality, ceremony and transparency . These fFirst, the evidence the judge sees at the court is what has been processed electronically. This sort of evidence is not equivalent to the original evidence. Thus, remote court hearing reduces the possibility of the judge having direct access to the original evidence. Second, due to non-contact of the subjects, the possibility for the judge to grasp the details and particulars of the court hearing decreases when they observe the voice, intonation, manner, expression and movement of the parties. In a remote court hearing without matching simultaneous HD video technology, judges’ hearing and observation could be hindered. However, direct observation, plus the knowledge of psychology and physiology to find the truth of the case, is the essence of direct hearing. Third, technical media, like a barrier, lowers both the psychological deterrent of the parties and the binding force of the court hearing. Accordingly, the probability of arbitrariness and falsity of the statements made by the parties in the hearing process increases. This especially true when the parties participate in the remote court hearing from their homes, as the casual living environment and the stately atmosphere of a court hearing constitute a striking contrast between venues. Casual dresses, lazy sitting postures, frequent exits, and other improper behaviours are likely to occur . Fourth,Remote court hearing has an impact of different degrees on the factors such as directness, orality, ceremony and transparency of the court hearing. The impact more likely runs counter to the fair value of the elements of the hearing. This means that although it is necessary to conduct remote court hearings during public health emergencies, the application of this system cannot be generalised.Only a litigation procedure is the source of legitimacy for a judgement or settlement . Even whFirst, in terms of technical operation, the court should be the builder and manager of the remote court hearing platform. By using public power to construct and manage the remote court hearing platform, the court is in a position to support the neutrality and security of the platform and enhance the trust of litigants. Second, remote court hearing should be conducted by video, and the application of video can ensure the clarity, synchronisation and real-time performance of the scenes. Third, in principle, remote court hearing should be a connection between court and court, that is, the subjects applying for remote court hearing should go to the court closest to them for hearing. The public, at different locations, may choose to go to the nearest court to exercise their right to sit in on a hearing. The court may also consider setting up special remote courts in its area for case parties to use. Of course, during public health emergencies, the parties will be required to restrict going outdoors as much as possible. When the litigants must participate in a remote court hearing at home, the judge should remind the parties of court hearing rules and inform them of the legal consequences of misconduct.In terms of start-up mode, the application of remote court hearing should focus on the parties, attention must be given to the principal position of the parties, and respect must be observed to the procedural options of the parties. Considering the equality of the parties, the start of remote court hearing should be based on the mutual choice of both parties. The court is not completely passive regarding initiation of remote court hearing. Instead, it gives proper play to its command power in terms of the hearing on the premise of the choice made by both parties. The court weighs the situation and determines what is a more appropriate court hearing mode based on the case’s dispute, evidence and characteristics of the procedure.In terms of scope of application, the scope where remote court hearing is applied expands with careful consideration from simple cases to those of average difficulty, which is a trend in line with the characteristics of the time and the practical needs of litigation societies. What kinds of cases are more suitable for remote court hearings still needs some practical observation and accumulation of cases. However, it is wrong to think that the application of remote court hearing has no rules to follow, and the following two factors deserve attention: In one sense, remote court hearings are applicable to cases where the authenticity of evidence is not controversial. Because remote court hearings impact on the form of existence of traditional evidence and increases the risk of losing authenticity of evidence, if both parties have doubts about the authenticity of the evidence, the application of remote court hearing undoubtedly aggravates their disputes. In another sense, remote court hearings are more suitable for legal trial cases in which direct contact between the subjects of proceedings is not necessary. As a whole, the trial grade from low to high is a trend of weakening the fact trial and strengthening the legal trial. Moreover, with higher trial grade, the phenomenon that the parties’ cross-region attendance on the hearing occasion is more common. Therefore, remote court hearings have more application space in the appeal trial cases or retrial cases.The COVID-19 outbreak has accelerated the application of remote court hearing. Remote court hearing results in an orientation of higher technology and flexibility with less paperwork and contact. These characteristics of remote court hearing help the litigant to access to justice, enhance the litigant procedure participation, and promote the litigation convenience, However, remote court hearing does not always bring about progress, and it also challenges court hearing factors such as the directness, orality, rituals and transparency of the court hearing. Therefore, the application of remote court hearing should not be generalised. By guiding the construction of remote court hearing platforms and technical operations, start-up mode and application scope, it will further strengthen the progress of remote court hearing, weaken its limitations and improve the validity of remote court hearing during public health emergencies.


There is an error in the third paragraph of the Introduction. The correct paragraph is: In people with hearing loss using assistive hearing technologies the ability to process ILD and ITD is limited [15]. Binaural summation effect, head shadow effect, and squelch effect are significantly smaller than in listeners with normal hearing [7]. The high variability in assistive technology parameters, e.g., processing times and channel numbers, and the asymmetry of hearing performance between the ears often result in bad outcome because of the wrong input in the auditory system caused by the hearing devices. Also synchronization technologies does not always help. Therefore, measuring binaural effects is challenging . The publisher apologizes for the error.


There was a reciprocal relationship between hearing and cognitiveabilities over time: better hearing in childhood was weakly associated with ahigher cognitive ability in middle age , and a higher cognitive ability in childhoodwas associated with better hearing in middle age . This latter, stronger effect was mediated byoccupational and health variables in adulthood. Our results point to thediscovery of a potentially life-long relationship between hearing and cognitiveabilities and demonstrate how these variables may influence one another overtime.Previous cross-sectional findings indicate that hearing and cognitive abilitiesare positively correlated in childhood, adulthood, and older age. We used anunusually valuable longitudinal dataset from a single-year birth cohort study,the National Child Development Study 1958, to test how hearing and cognitiveabilities relate to one another across the life course from childhood to middleage. Cognitive ability was assessed with a single test of general cognitiveability at age 11 years and again with multiple tests at age 50. Hearing abilitywas assessed, using a pure tone audiogram, in childhood at ages 11 and 16 andagain at age 44. Associations between childhood and middle-age hearing andcognitive abilities were investigated using structural equation modelling. Wefound that higher cognitive ability was associated with better hearing(indicated by a lower score on the hearing ability variables); this associationwas apparent in childhood ( The number of interdisciplinary studies examining the relationship between auditoryand cognitive processes is on the rise. This area of study, sometimes termedCognitive Hearing Science or Auditory Cognitive Science, fills the explanatory gapbetween “pure” cognitive and auditory sciences . The ling’ . This measure of general cognitive ability ishighly correlated with intelligence quotient (IQ) scores derived from single IQtests (Fluid intelligence (abstract reasoning or the ability to solve unfamiliar problems),processing speed (the time required to process information), visuospatial ability, crystallisedability (learned knowledge and experience), and memory are all types of cognitiveability. These domains, although conceptually distinct, tend to be positivelyassociated . Indeed,IQtests . OnaverIQtests . There iIQtests . DespiteIQtests .Hearing abilities can be assessed on various levels from the simplest auditorydetection tasks (e.g. pure-tone audiometry), conceptually more complicated auditorydiscrimination (e.g. the ability to differentiate between auditory stimuli), tocomprehension (e.g. the ability to understand the meaning of speech under variousauditory conditions). It is reasonable to assume that abilities at the higher end ofthis auditory hierarchy, such as comprehension, require greater engagement oftop-down processes particularly when auditory conditions are sub-optimal . ResearcDeaf children with appropriate exposure to sign language can follow typicaldevelopmental trajectories  and perfOther studies of children with unilateral hearing loss or milder forms of hearingimpairment (i.e. >15 and <35 dB hearing loss [HL]) show that these conditions,which can remain undetected and untreated , may alsr  =  0.3 and r  =  0.6 (though these weresometimes associations between latent traits and not correlations between two singlevariables). Further investigations have compared different forms of auditoryprocessing and their relation to cognitive function. For instance, Deary  are tracked overtime and are therefore also present at later life stages. This possibility, whichemphasises the stability of individual differences in hearing and cognitiveabilities, contrasts with the prediction made by the common cause hypothesis , which pIn the present study we took advantage of a unique research opportunity todemonstrate that there is a life-long – from childhood to middle age – reciprocaland dynamic relationship between hearing and cognitive abilities. The NCDS is alongitudinal cohort study of individuals living in Scotland, England, and Wales whowere born during one week in 1958. It includes assessments of hearing and cognitiveabilities in childhood and in middle age. We note here that, because the sample wasdrawn from the general population, the proportion of participants with mild tosevere hearing loss is low and therefore, specific mechanisms linking hearing losswith cognitive ability could not be tested. Nevertheless, participants showsignificant variance in hearing threshold levels in childhood and adulthood, albeitpredominantly within the normal hearing range. Using these data, we firstly testedthe “tracking hypothesis” that is, whether associations between hearing andcognitive abilities in childhood are tracked over time and therefore account forassociations between those same variables in middle age. Secondly, we tested forso-called “cross-lagged” effects : from chThe NCDS is a longitudinal study of people living in Scotland, England, and Waleswho were born in a single week in March 1958 . The stuVerbal informed consent was sought from respondents or respondents’ parents foreach survey, written consent was recorded at the biomedical survey at age 44.Ethical approval was obtained from the South East and London multicenterresearch ethics committees . See r  =  0.93) with an IQ-type test used forsecondary school selection  years usinga pure tone audiogram (performed by air conduction) in each ear. This methodmeasures hearing threshold levels for a range of frequencies. At ages 7, 11,and 16 the audiogram was conducted in locally available audiometerfacilities and included frequencies of 0.25, 0.5, 1, 2, 4, and 8 kHz. Wecreated a latent variable representing childhood hearing ability usinghearing threshold levels at ages 11 and 16. Because hearing losses aretypically smaller and therefore harder to detect at low frequencies e.g. we did nWe identified covariate variables that might confound the association betweenhearing and cognitive abilities in childhood, or potentially mediate theassociation between childhood cognitive ability and middle-age hearingability. Potentially confounding variables included sex, history of middleear dysfunction, and childhood social class. Results from an otoscopicexamination of each ear at age 11 were used as a proxy measure of middle eardysfunction. As has been done previously  participDistance visual acuity was recorded at age 11 using a conventional Snellenchart at 6.1 m, and at age 44 using a LogMAR crowded test at 1.5 m . Using best achieved distancevisual acuity in each eye (corrected if prescribed) and a cut-off appliedpreviously with this cohort , wecateOwing to the long-running nature of the NCDS, there are missing data on somevariables. We excluded participants from the analytical sample if they hadmissing data on the hearing or cognitive ability variables at ages 11 or 16. Inorder to reduce the potential effect of profound hearing loss on our results, weexcluded participants who were identified as deaf at age 44, or had a history ofillness associated with hearing loss . We further excluded participants withmissing data on independent (exogenous) variables; these were sex, history ofmiddle ear dysfunction, and childhood social class . Participants withmissing data on history of meningitis or maternal rubella were also excluded.These exclusions resulted in an analytical sample of 6,059 participants. Theflow chart in We examined the association between childhood and middle-age hearing andcognitive abilities using structural equation modelling (SEM). An advantage ofSEM is that it is possible to simultaneously model manifest and error-freelatent variables and the potential relationships between them. Model developmentprogressed in two stages. We firstly ran two preliminary cross-sectional models:one of childhood hearing threshold and cognitive ability and another ofmiddle-age hearing threshold and cognitive ability. This approached allowed usto test whether the hearing and cognitive constructs could be modelled as latentvariables and to test for cross-sectional associations between them. We usedhearing threshold levels of left and right ears at ages 11 and 16 as indicatorsof overall childhood hearing threshold. We used hearing thresholds at 1 and4 kHz for each ear as indicators of overall hearing threshold at age 44.Cognitive ability at age 50 was modelled using three indicators of verbalfluency, memory, and processing speed. We summed scores on the immediate anddelayed recall tests to create a single indicator of memory and used totalnumber of letters scanned on the letter cancelation test as an indicator ofprocessing speed. Following this first step, we ran three main longitudinalmodels estimating associations between childhood and middle age hearingthresholds and cognitive abilities. These models are summarized in p-values from these models for multiplecomparisons using the Benjamini–Hochberg False Discovery Rate (FDR) correction with the aid of Rpackages dplyr  wereestimated using maximum likelihood (ML) estimation. For Model 3, WLSMVestimation was used, as otherwise it was too computationally demanding for MLestimation owing to the multiple categorical mediators in this model. With WLSMVestimation, categorical mediators are modelled as continuous latent responsevariables and path estimates are modelled using linear regression . Models rrection. P-valuerrection. Followirrection: β <0.2 es dplyr , tidyr and at age 16 . Correlations between hearingthresholds at different ages (same or different frequencies) were moderate in effectsize . Performance on the general cognitive abilitytest at age 11 was significantly negatively correlated with hearing thresholds ateach frequency and age; the effect sizes of these correlations was small.Hearing thresholds at age 44 were significantly positively correlated across ears andfrequencies . Scores on the four cognitive abilitytests at age 50 were significantly positively correlated with each other. There was a significant negative correlation betweenmost cognitive ability test scores at age 50 and hearing thresholds at age 44 withthe exception of letter cancellation speed and hearing thresholds at 1 kHz.The relationship between hearing and cognitive abilities in childhood and middle ageis illustrated in Comparisons of participants with normal vision and visual impairment indicated nosignificant differences in hearing threshold levels at age 11 or 44 (seeSupplementary Tables 6 and 7).r  =  -0.117, p < 0.001) indicating that ahigher cognitive ability was associated with a lower overall hearing threshold(i.e. more sensitive hearing).We firstly ran a SEM of childhood hearing threshold and cognitive ability (Model0A). Hearing threshold in childhood was modelled as a single latent factor;hearing thresholds of each ear at ages 11 and 16  weretreated as factor indicators. Cognitive ability in childhood was modelled as anobserved variable using the general cognitive ability test score at age 11. Wefound that the initial model of childhood hearing threshold and cognitiveability, which allowed residual correlations between hearing threshold levels ofthe same frequency to correlate (between ears and measurement occasions) did notfit the data well: CFI =  0.659, TLI  =  0.512, RMSEA  =  0.206. Poor fitindices are commonly encountered when factors have a high number of indicators, as was r  =  -0.299,p < 0.001). Results of these models are shown inSupplementary Figure 1.Next, we ran a model of middle-age hearing threshold and cognitive ability (Model0B). This model fit the data well: CFI  =  0.996, TLI  =  0.991,RMSEA  =  0.024. Factor loadings for cognitive ability in middle age weresignificant and ranged between 0.216 and 0.536. Factor loadings for hearingthreshold in middle age were also significant and ranged between 0.508 and0.483. Residuals of hearing thresholds for the same ear or for the samefrequency were allowed to correlate. Middle-age cognitive ability and middle-agehearing threshold were significantly correlated . Childhood cognitive ability significantlypredicted middle-age cognitive ability β  =  0.624,p <0.001 and childhood hearing threshold significantlypredicted middle-age hearing threshold β  =  0.430,p <0.001, suggesting that these traits were relativelystable from childhood to middle age. The cross-lagged effect from childhoodcognitive ability to middle-age hearing threshold was significantβ  =  -0.163, p <0.001 and indicatedthat a higher cognitive ability in childhood was associated with better hearingin middle age. The cross-lagged effect from childhood hearing threshold tomiddle-age cognitive ability was smaller but also significantβ  =  -0.076, p  =  0.001 and indicated thatbetter hearing in childhood was associated with a higher cognitive ability inmiddle age.Model 1, with no potentially confounding or mediating variables provided anadequate fit to the data CFI  =  0.970, TFI  =  0.955, RMSEA  =  0.046.Estimates from Model 1 are shown in Supplementary Table 9. In childhood, having a father in the“professional” relative to a “manual” childhood occupational social class wasassociated with poorer hearing; having a father in the “professional” relativeto any other childhood occupational social class was associated with higherchildhood cognitive ability. Being female was associated with a higher childhoodcognitive ability but was unrelated to childhood hearing. Middle ear dysfunctionwas related to poorer childhood hearing. The correlation in Model 2 betweenchildhood hearing threshold and cognitive ability was only slightly reduced fromr  =  -0.120, p <0.001 (in Model 1) tor  =  -0.098, FDR p  =  0.001. Theremaining parameter estimates including the correlation between middle-agehearing threshold and cognitive ability were largely unchanged.Model 2, which controlled for potentially confounding variables in childhood,also fit the data adequately CLI  =  0.962, TFI  =  0.950, RMSEA  =  0.039.Estimates from Model 2 are shown in Supplementary Table 10. Childhood cognitive ability wassignificantly related to each of the potentially mediating variables assessed inmiddle age. Specifically, a higher childhood cognitive ability was related, atage 44, to a lower risk of diabetes, more frequent physical activity, greateralcohol consumption, a more professional occupation, less smoking, lessoccupational noise exposure, a lower BMI, and lower blood pressure. Potentiallymediating variables that were also associated with poorer middle-age hearingincluded history of diabetes, more smoking, greater occupational noiseexposure, and a higher BMI. Both cross-lagged effects, fromchildhood cognitive ability to middle-age hearing threshold and from childhoodhearing threshold to middle-age cognitive ability were attenuated tonon-significance in this model. The correlation between middle-age hearingthreshold and cognitive ability was slightly reduced but remained significantr  =  -0.125, FDR p  =  0.024.Finally, in Model 3 we tested whether the cross-lagged association betweenchildhood cognitive ability and middle-age hearing threshold was mediated by aset of occupational, demographic, lifestyle and health factors assessed inmiddle age. This model had an adequate fit to the data CLI  =  0.962,TFI  =  0.954, RMSEA  =  0.040. Estimates from Model 3 are shown in Supplementary Table 1In subsidiary analysis we additionally tested whether the relationship betweenchildhood hearing threshold and middle-age cognitive ability was mediated by anyof the occupational, demographic, lifestyle or health variables. Results fromthis analysis are shown in Supplementary Table 1Secondly, the factor loading of processing speed on the middle-age generalcognitive ability latent variable was low. To test for associations between thehearing threshold variables and processing speed we re-ran Model 1 replacingmiddle-age cognitive ability with the processing speed variable. Results fromthis analysis are shown in Supplementary Table 1Finally, a large proportion of the original NCDS sample was excluded from theanalytical sample due to missing data on the childhood cognitive ability orhearing variables. To test whether this approach had biased our results, were-ran Model 1, including participants with missing data on the these variables, note that participants with no data on any of thechildhood cognitive ability or hearing variables were still excluded . Parameter estimates from analysis with this larger sample  Betterhearing  was associated with aslightly higher cognitive ability; this association was apparent in cross-sectionalresults in childhood and in middle age. 2) Between-person differences in hearing andcognitive abilities were relatively stable from childhood to middle age. 3) Therewas a cross-lagged association between higher childhood cognitive ability to bettermiddle-age hearing ability, and a smaller but still significant association betweenbetter childhood hearing ability and higher middle-age cognitive ability. 4)Potentially confounding variables  did not fully account for the relationship between hearingand cognitive abilities in childhood. 5) The relationship between childhoodcognitive ability and middle-age hearing ability was statistically mediated byoccupational and health variables in adulthood: occupational noise exposure, BMI,history of diabetes, and smoking status. 6) The relationship between hearing andcognitive abilities in middle age was not fully explained by childhood hearing andcognitive abilities 6.p-values, even for very smalleffects . However, in the present study,assessments of hearing abilities were not equivalent in childhood and middle age.Relative to assessments in childhood, middle-age hearing ability was assessed usinga shorter audiogram with fewer frequencies. The true associations between childhoodand middle-age hearing abilities may differ from those documented here; it ispossible that repeated assessment with a more sensitive instrument would detectsubtle changes in hearing abilities that were not captured in the present study.We found that between-person differences in hearing and cognitive abilities wererelatively stable from childhood to middle age. Whereas the stability of cognitiveability across the life course has been documented by others , less haGeneral cognitive ability was also assessed with different types of tests inchildhood and adulthood. This difference might have affected the observedassociations between cognitive and hearing abilities. Specifically, indicators ofgeneral cognitive ability in middle age included two tests that are sensitive tocognitive ageing effects, namely verbal memory and processing speed. We cannot ruleout that these cognitive ability domains were more strongly negatively associatedwith hearing loss in middle age and that a weaker association would be observed ifan IQ-type test had been used.In addition to tracking the correlation between hearing and cognitive abilities fromchildhood to middle age, we tested for potential cross-lagged effects. The positiveassociation between childhood cognitive ability and middle-age hearing abilityobserved here corroborates findings from our previous study with older adults, inwhich a higher childhood cognitive ability was related to a lower risk of hearingimpairment in older age . Howeverβ  =  -0.076) association between betterchildhood hearing ability and higher middle-age cognitive ability. This findingcould indicate that any influence of hearing loss on cognitive development  were conducted in locally availablefacilities and procedures were not standardised across sites . TherefoIn summary, this study has for the first time demonstrated a life-long – fromchildhood to middle age – reciprocal and dynamic relationship between hearing andcognitive abilities. These new findings demonstrate the value of applying alife-course perspective to Cognitive Hearing Science research. Further, they opentwo new research topics: (1) studies with children could examine how associationsbetween hearing and cognitive abilities, established at early stages of development,play out in adolescence and adulthood, and how these variables relate to otherimportant life outcomes including physical health and health behaviours, and (2)research into hearing and cognitive abilities in older age should incorporate thepotential contribution of pre-morbid hearing and cognitive abilities to thisrelationship.Click here for additional data file.Supplemental material, sj-docx-2-tia-10.1177_23312165211053707 for AssociationsBetween Hearing and Cognitive Abilities From Childhood to Middle Age: TheNational Child Development Study 1958 by Judith A Okely, Michael A Akeroyd andIan J Deary in Trends in Hearing