To compare intraocular pressure (IOP) measurements with Goldmann applanation tonometry (GAT), ocular response analyzer (ORA), dynamic contour tonometer (DCT), and Corvis ST (CST) in healthy subjects.  In a prospective, observational study, IOP measurements with GAT (GAT-IOPc), ORA (IOPcc), DCT (DCT-IOP), and CST (bIOP) were performed and analyzed in 94 healthy subjects. P < 0.001). Mean bIOP was 13.5 ± 2.4 mmHg that was slightly higher but not significantly different from GAT-IOPc (P=0.146). Correlation analysis of IOP values and central corneal thickness (CCT) revealed a negative correlation between GAT-IOPc and CCT . However, IOPcc, DCT-IOP, and bIOP showed no significant correlation to CCT. Only bIOP revealed a weak but significant age dependency .  Mean age of the participants was 45.6 ± 17.2 years (range 18 to 81 years). Mean GAT-IOPc was 12.9 ± 2.4 mmHg, mean DCT-IOP was 16.1 ± 2.6 mmHg, and mean IOPcc was 15.6 ± 3.3 mmHg. DCT-IOP and IOPcc were significantly higher than GAT-IOPc ( All tonometry devices showed a good agreement of biomechanical corrected IOP values with GAT-IOPc. As no influence of CCT on IOPcc, DCT-IOP, and bIOP was detectable, the used correction algorithms appear to be appropriate in these tonometers in the clinical setting. The highest agreement was found between GAT-IOPc and bIOP. However, bIOP weakly correlated with participants' age. Further studies are needed to elucidate the role of bIOP for IOP measurement. Glaucomatous optic neuropathy is one of the leading causes of irreversible blindness worldwide , 2. EstiFor many years, Goldmann applanation tonometry (GAT) is the gold standard for IOP measurement ,13–15. DThe Pascal Dynamic Contour Tonometer , the Reichert Ocular Response Analyzer , and the Dynamic Scheimpflug Analyzer Corvis ST  are three relatively new methods designed to be less affected by corneal biomechanical properties.Briefly, the DCT is a contact method which is mainly based on the principle that by matching the contour of the cornea, the pressure on the outside correlates to the pressure on the inside of the globe . In contBefore introducing these newer instruments into the clinical setup, their correlation with GAT should be evaluated. Therefore, in the present study, these tonometers were used in healthy subjects and measurement results of corrected GAT-IOP (GAT-IOPc) were compared to IOP values determined by DCT (DCT-IOP), ORA (IOPcc), and CST (bIOP).This prospective study was conducted at the Department of Ophthalmology of the University Hospital Carl Gustav Carus, Technical University Dresden, Germany. The study protocol was approved by the local ethics committee and followed the Declaration of Helsinki. All subjects signed a written informed consent before participation. Inclusion criteria were age over 18 years and the absence of any corneal pathology, previous ocular surgical interventions or injuries, contact lens wear, glaucoma, and systemic connective tissue diseases. Ninety-six healthy voluntary subjects were recruited. Participants had to pass a complete ophthalmic examination including slit lamp biomicroscopy, GAT, and fundus biomicroscopy. GAT measurements were taken as one reading performed by an experienced investigator according to standard protocols , 23. ConThe DCT is a contact tonometer using a piezo-resistive sensor tip attaching the cornea concavely while the curvature of the cornea is not affected. Therefore, the natural shape of the cornea is maintained during measurement and a smaller influence of corneal biomechanical properties than in GAT is considered. Details of the measurement principle were described elsewhere , and a gThe ORA is a noncontact tonometry device. During the measurement, a rapid jet of air of increasing intensity induces a bidirectional applanation process of the cornea. An infrared beam is used to monitor the corneal deformation. From the differences of the acting pressures to achieve defined corneal deformation states, the device calculates and provides four variables: the Goldmann-correlated IOP (IOPg), the corneal-compensated IOP (IOPcc), the corneal resistance factor (CRF), and the corneal hysteresis (CH). Details are described elsewhere , 23, 28.The CST measures the IOP and evaluates the dynamic response of the cornea to an air puff. During measurement, a two-dimensional image of the cross section of the deforming cornea is created using a high-speed Scheimpflug camera and amplitude, duration, and velocity of the corneal applanation are recorded –21, 29. P value <0.05 was considered as statistical significant. Bland–Altman plots were designed using MedCalc .All data were compiled using a spreadsheet software  and transferred to SPSS Version 24 . IOP values of all tonometry devices were normally distributed (Shapiro–Wilk test) and analyzed using ANOVA for repeated measurements. Mean IOP values, standard deviations of the means, and the amount of IOP differences between the tonometry devices were indicated. Correlations between IOP and CCT as well as between IOP and age were assessed using Pearson correlation analysis. A μm, and mean GAT-IOPc was 12.9 ± 2.4 mmHg. Mean DCT-IOP was 16.1 ± 2.6 mmHg, which was significantly higher than GAT-IOPc (P < 0.001). Also, IOPcc was significantly different from GAT-IOPc (P < 0.001) and showed a mean value of 15.6 ± 3.3 mmHg. Mean bIOP was 13.5 ± 2.4 mmHg and also higher but not significantly different from GAT-IOPc (P=0.146). Data are summarized in Tables The present study initially included 96 eyes of 96 healthy subjects. Two eyes were excluded from further analysis due to incomplete data acquisition. Mean age of the remaining 94 participants was 45.6 ± 17.2 years (range 18 to 81 years). Thirty-nine subjects were female, and 55 were male. Mean CCT was 553 ± 33 r = −0.347, P=0.001, Correlation analysis revealed a significant association between GAT-IOPc and CCT . The 95% limits of agreement ranged from 1.2 mmHg to −7.6 mmHg . The 95% limits of agreement ranged from 4.6 to −5.9 mmHg , and healthy subjects . In thisAlthough DCR-IOP , 35, 39,There is no doubt about the influence of corneal thickness and biomechanics on IOP measurement –53. SincOn the other hand, results concerning age dependency are inconsistent. Joda et al. reported a weak age dependency of uncorrected CST-IOP in a study with a high case number. According to this investigation, an algorithm correcting CST-IOP for CCT and age is mandatory . The impLooking at age dependency of uncorrected CST-IOP, results are inconsistent. Some authors found no age correlation of CST-IOP , 59 whilAn important criterion for the quality of IOP measurement represents the stability of results with repeated measurements. Tejwani et al. reported a lower coefficient of variation for CST-IOP (4.61%) compared to DCT (7.18%) and IOPcc (11.06%) . In addiIn conclusion, all used tonometry devices revealed a good consistency of IOP results with GAT-IOPc. Except GAT-IOPc, no influence of CCT was detectable so that the used correction algorithms appear to be appropriate to compensate varying corneal thickness. The highest accordance was found between GAT-IOPc and bIOP. Nevertheless, as only this parameter showed an age correlation, the superiority of the bIOP remains questionable. Further studies are certainly needed to elucidate the role of bIOP for IOP measurement.


As the proportion of older adults in the world’s total population continues to grow, the deleterious downstream health economic outcomes of age-related hearing loss are steadily becoming more prevalent. While recent research has shown that age-related hearing loss is the single greatest modifiable risk factor for dementia, the rate of hearing aid use remains low in many countries across the globe. Reasons for poor uptake are multifactorial and likely involve a combination of factors, ranging from increasing costs of hearing aid technology to lack of widespread insurance coverage. This paper aims to first identify the current state of hearing aid access across the world using eight representative countries as examples. We then provide recommendations on how to facilitate greater access to hearing aids for consumers by addressing areas in regulation, technology, reimbursement, and workforce.


A large proportion of older adults experience hearing loss. Yet, the impact of hearing loss on the aging brain, particularly on large-scale brain networks that support cognition and language, is relatively unknown. We used resting-state functional magnetic resonance imaging (fMRI) to identify hearing loss-related changes in the functional connectivity of primary auditory cortex to determine if these changes are distinct from age and cognitive measures known to decline with age . We assessed the functional connectivity of Heschl’s gyrus in 31 older adults (60–80 years) who expressed a range of hearing abilities from normal hearing to a moderate hearing loss. Our results revealed that both left and right Heschl’s gyri were significantly connected to regions within auditory, sensorimotor, and visual cortices, as well as to regions within the cingulo-opercular network known to support attention. Participant age, working memory, and processing speed did not significantly correlate with any connectivity measures once variance due to hearing loss was removed. However, hearing loss was associated with increased connectivity between right Heschl’s gyrus and the dorsal anterior cingulate in the cingulo-opercular network even once variance due to age, working memory, and processing speed was removed. This greater connectivity was not driven by high frequency hearing loss, but rather by hearing loss measured in the 0.5–2 kHz range, particularly in the left ear. We conclude that hearing loss-related differences in functional connectivity in older adults are distinct from other aging-related differences and provide insight into a possible neural mechanism of compensation for hearing loss in older adults. Beginning at age 50, as many as 15% of adults in the United States have at least a mild hearing loss, with this rate doubling every decade, such that by the seventh decade approximately two-thirds of adults have a hearing loss . These tRecent work has linked age-related hearing loss to a roughly two-fold increased risk for cognitive decline and dementia, with hearing loss likely preceding the onset of cognitive decline by 5–10 years . In a ladecreases associated with hearing loss in primary auditory cortex  and other temporal lobe structures  has identified differences between older adults with and without hearing loss in response to auditory stimuli. In a study utilizing tones, there was reduced activation in subcortical auditory regions with increasing hearing loss but no relationship with activation in auditory cortex  . ConversResting-state fMRI can be used to disentangle general age effects from the effects of age-related hearing loss on brain function. This technique measures functional connectivity of brain networks in the absence of any task, avoiding introducing task- or stimuli-related confounds, yet still capturing the brain networks that are modulated during language and cognitive tasks . StudiesHeschl’s gyrus is a key target in investigating the effects of age-related hearing loss due to its role in auditory processing and the conflicting findings regarding the structural and functional impact of hearing. The structural and effective connectivity of Heschl’s gyrus to nearby temporal auditory processing regions has been explored in humans . HoweverIn the present study, functional connectivity was characterized from left and right Heschl’s gyrus to all voxels in the cerebrum in 31 typical older adults . Functional connectivity between each hemisphere’s Heschl’s gyrus and all cerebral voxels were computed and correlated with participant hearing ability, controlling for age, working memory, and processing speed, to determine if hearing loss is related to changes in brain functional connectivity that are distinct from other age-related changes. Given the findings of previous literature, we predicted that age-related hearing loss will be associated with increases in functional connectivity between Heschl’s gyrus and regions in the language, cingulo-opercular, and visual networks, after controlling for participant age and cognitive performance. A within-subjects approach was utilized instead of a younger versus older adult group comparison because our focus is on how age-related hearing loss in particular may be affecting functional connectivity results in typical aging. Age-related hearing loss typically has quite different onset trajectories, frequencies most affected, and neuroanatomical and structural mechanisms than hearing loss in younger adults  . We alsor = −0.068, p = 0.717). No participant expressed indications of depression, as measured by the 15-item Geriatric Depression Scale where a score greater than five suggests depression . Written informed consent was obtained from each participant in accordance with Arizona State University’s Institutional Review Board and the US Federal Policy for the Protection of Human Subjects guidelines. Participants were compensated monetarily for their efforts.Participants were 31 adults aged 60–80 years  recruited from the greater Phoenix area. All participants were native English-speaking, right-handed as determined by the Edinburgh Handedness Inventory [mean (sd) = 94.6 (16.2)], and free from dementia, as determined by the Mini Mental Status Exam, score ≥ 27 . MMSE scores did not significantly correlate with participant age  which was read by a clinical neuroradiologist to identify any possible neural abnormalities or etiologies that may affect the hearing or cognitive measures collected in the present study; all participants passed this MRI screening.Pure-tone audiometry (PTA) was used to assess participant hearing ability in both ears and was conducted using a GSI 18 Audiometer and supra-aural headphones in a quiet, but not sound-attenuated, testing room. Assessors were trained by a clinical audiologist. First, the outer ear and ear canal were checked for excess cerumen using an otoscope. No participants presented with blocked canals. Testing then began in the right ear at 1 kHz at 50 dB HL using a pulsed tone. The intensity was decreased by 10 dB for every accurately perceived tone and increased by 5 dB for every missed tone, until the participant responded twice in the affirmative for a single intensity level; this value was recorded as the threshold for that frequency. The following frequencies were tested: 0.250, 0.500, 1, 2, 4, and 8 kHz. If the participant wore hearing aids, hearing acuity was evaluated unaided. MRI was also conducted unaided. Five participants reported wearing hearing aids.Wechsler Adult Intelligence Scale 4th edition (WAIS-IV) were administered to collect measures of working memory and processing speed  = 2.3 ms, TE (long) = 4.6 ms, flip angle = 10°, FOV = 240 × 240, matrix = 80 × 80, voxel size = 3 mm × 3 mm × 3 mm, 52 sagittal slices, acquisition time = 1 min 22 s. A T1 MPRAGE anatomical scan also was acquired for each participant with the following parameters: TR = 6.74 s, TE = 3.10 ms, flip angle = 9°, FOV = 270 × 253, matrix = 256 × 256, voxel size = 1.1 mm × 1.1 mm × 1.2 mm, 170 sagittal slices, acquisition time = 5 min 34 s.http://www.nitrc.org/projects/artifact_detect) was used to compute a composite motion measure. This composite motion measure was used to identify and scrub volumes with motion greater than 2 mm or with changes in the global signal mean greater than a Z-value of 9 . These volumes were modeled out at the individual participant level using nuisance regressors . The CONN toolbox utilizes an aCompCor  regression to reduce physiological noise associated with cerebrospinal fluid and white matter by extracting five principle components from each tissue type . Heschl’s gyri ROIs  were provided in the CONN toolbox and are from the FSL Harvard-Oxford Atlas maximum likelihood cortical atlas. To characterize the average functional connectivity from left and right Heschl’s gyri across the cortex, ROI-to-voxel connectivity was assessed using two-sided, one-sample t-tests thresholded at voxelwise p < 0.001 uncorrected and cluster-level p < 0.05 FDR. To compare changes in connectivity associated with hearing loss to that of age and cognitive measures commonly affected by age , the following two-sided correlations were conducted with a threshold of voxelwise p < 0.001 uncorrected and cluster-level p < 0.05 FDR: (1) the correlation of hearing ability with connectivity from left Heschl’s gyrus and from right Heschl’s gyrus to all voxels, controlling for age, working memory, and processing speed, and (2) the correlations of age, working memory, and processing speed with connectivity from left Heschl’s gyrus and right Heschl’s gyrus, respectively, to all voxels, controlling for hearing ability.Functional connectivity was computed between anatomically defined ROIs (regions of interest) of left and right Heschl’s gyrus and all voxels of the cortex. Pearson correlation coefficients were calculated between the average time course within each ROI and the time courses of all other cerebral voxels; correlation coefficients were then Fisher transformed  or MMSE scores . Hearing ability also did not significantly correlate with WMI scores  or PSI scores .Hearing ability was quantified as the average threshold between all tested frequencies over both ears, where a higher threshold indicates greater hearing loss [mean (sd) = 26.76 (12.01) dB, range = 6.25–52.92 dB, corresponding to a range of hearing abilities from normal hearing to moderate hearing loss; Functional connectivity  from left and right Heschl’s gyrus to all cerebral voxels is characterized in Similar to the right, left Heschl’s gyrus was significantly and positively functionally connected to bilateral Heschl’s gyri, as well as regions extending the length of the superior temporal gyri. It is notable though that the bilateral temporal regions significantly functionally connected to left Heschl’s gyrus extend more posteriorly and inferiorly into the bilateral middle temporal gyri than observed with right Heschl’s gyrus. Left Heschl’s gyrus was also significantly connected to bilateral pre-central and post-central gyri. Compared to right Heschl’s gyrus, functional connectivity from left Heschl’s gyrus covered a larger portion of visual areas and extended into medial and posterior occipital cortex, including lingual and lateral occipital gyri, respectively. Significant connectivity was also observed to regions of the cingulo-opercular network, including bilateral insula, anterior cingulate cortex, and supplementary motor areas. A region within the left superior and middle frontal gyri  exhibited negative functional connectivity to left Heschl’s gyrus.To examine the effects of age-related hearing loss on Heschl’s gyrus connectivity compared to age and cognitive measures, functional connectivity between Heschl’s gyrus and all cerebral voxels was correlated with hearing loss. The analysis correlating hearing loss with connectivity, controlling for age, WMI, and PSI is shown in To explore the contributions of high-frequency hearing loss and hearing loss within the speech frequency range to the results reported above, we ran additional analyses correlating hearing loss with functional connectivity of left and right Heschl’s gyrus, controlling for age, WMI, and PSI. The difference from the previous analyses is that the measure of hearing loss was (1) the PTA thresholds only averaged across the high frequencies tested (4 and 8 kHz), and then (2) with the measure of hearing loss being the PTA thresholds only averaged across the speech frequencies tested (0.5–2 kHz). These frequency ranges were selected based on previous epidemiological work in older adults  and AmerHowever, hearing loss within the speech frequency range was significantly correlated with functional connectivity between right Heschl’s gyrus and a group of voxels in the dorsal anterior cingulate and supplemental motor area  and by hearing loss in the left (but not right) ear. These findings characterize the extensive functional connectivity of Heschl’s gyrus in older adults and point to a possible difference regarding its connectivity with the cingulo-opercular network that may serve as a compensatory mechanism in response to age-related hearing loss.Our findings illustrate that bilateral Heschl’s gyrus is highly functionally connected to primary somatosensory and motor cortices, aligning with prominent models of auditory speech processing and auditory-motor integration . We alsoOur findings also reveal that both Heschl’s gyri are significantly functionally connected to regions within the cingulo-opercular network. Functional connectivity of Heschl’s gyrus to regions within the cingulo-opercular network may offer insight into a mechanism that supports auditory attention processes. Previous work suggests that the cingulo-opercular network is involved in goal-driven behaviors through the initiation and top-down maintenance of task sets, adjusting performance in response to errors to optimize performance , 2008. TOur study revealed that age-related hearing loss was positively correlated with functional connectivity from right Heschl’s gyrus to the dorsal anterior cingulate. In other words, as the level of hearing loss increases so too does the functional connectivity between right auditory cortex and the dorsal anterior cingulate, a region within the cingulo-opercular network. To confirm that the dorsal anterior cingulate voxels that we identified as having increasing connectivity with right Heschl’s gyrus as a function of hearing loss are in fact part of the cingulo-opercular network, we used these dorsal anterior cingulate voxels as an ROI and then determined which voxels throughout the cerebrum exhibited significant functional connectivity to them. This exploration of our results indicated that these voxels are significantly functionally connected to the surrounding anterior cingulate and supplementary motor area cortex, as well as bilateral insula , which nThe small body of previous literature using resting-state fMRI to explore the impact of age-related hearing loss on functional connectivity is equivocal. A few studies report increased connectivity between Heschl’s gyrus and the visual MT+ area, as well as differences within the dorsal attention and default mode networks . HoweverWhile differences in methodologies may explain the discrepancies between our findings and other studies using resting-state functional connectivity measures, our results align well with task-based fMRI findings of degraded speech comprehension (which may simulate hearing-loss effects in older adults). Several task-based fMRI studies demonstrate that activation within regions of the cingulo-opercular network is increased in response to acoustic degradation of speech stimuli in both young and older adults, when additional attentional resources are required to maximize speech comprehension performance . AdditioThe resting-state and task-based fMRI studies that examined hearing loss mentioned above either averaged hearing measures across both ears or from the better ear. But examining each ear’s thresholds separately may provide more detail regarding how age-related hearing loss is related to functional brain changes. The well-known right ear advantage in hearing sensitivity and speech perception has been identified across the lifespan  was associated with increased functional connectivity between right Heschl’s gyrus and dorsal anterior cingulate cortex in the cingulo-opercular network. Conversely, age, working memory, and processing speed were not significantly correlated with functional connectivity of Heschl’s gyri, once controlling for hearing ability. Together our findings reveal age-related hearing loss differences in Heschl’s gyrus functional connectivity that may reflect compensatory attention-related mechanisms for auditory processing. Future studies are certainly needed to fully characterize the effects of age-related hearing loss versus other age-related factors on functional connectivity in older adults, but the present study provides clear evidence that studies of functional connectivity in older adults should consider how age-related hearing loss may be contributing to their results.The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher.Written informed consent was obtained from each participant in accordance with Arizona State University’s Institutional Review Board and the US Federal Policy for the Protection of Human Subjects guidelines. Participants were compensated monetarily for their efforts.MF, SS, LB, and CR contributed to the design of the study. MF and AH were critical in implementing and analyzing the data. All authors contributed to data interpretation and manuscript preparation.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.


Coping strategies used by adolescents has an important role in preventing or decreasing their stresses and also increasing their well-beings. This study aimed at evaluating the coping capacity and well-being of adolescent students with hearing loss in mainstream schools and also the correlations between their coping strategies and positive characteristics of well-being .In this correlational study, 122 adolescent students with hearing loss were randomly selected from mainstream schools. Data collection was done by EPOCH Measure of Adolescent Well-Being and the Ways of Coping Questionnaire (WAYS). The Spearman correlation coefficient was used for determining the correlations between variables.The mean scores of using different coping strategies varied from 1.36 in problem solving to 1.44 in seeking support. Among the positive characteristics of well-being, happiness had the lowest (11.04) and connectedness showed the highest score (12.33). The findings also showed a significant correlation between all coping strategies and EPOCH, however there was a strong positive correlation between total coping strategy score and perseverance (0.648) and happiness (0.629).Based on the results, the score of happiness in students with hearing loss was the lowest among positive characteristics of well-being and also happiness showed a strong association with total scores in coping strategies. Accordingly, interventional studies are needed to examine whether training students with hearing loss to use coping strategies is effective in increasing their happiness and overall well-being. Adolescence is a period of significant changes in biological, psychological, socio-emotional and cognition development that can be associated with behavioral, social and health problems . ThroughCoping strategies mediates the relationship between predictor measures of functional limitations and perceived visibility of condition and outcome measures of disability-specific psychosocial adjustment and life satisfactions of people with disability . Livneh Adolescents with hearing loss are often faced with the additional challenge of adapting to hearing world, where communication and also access to information is difficult . Those eExposure to different stressors is typically associated with low levels of well-being . ChildrePsychologists have always been interested in the risk and/or supportive factors that impact individual’s well-being. Studies  on copinBased on relevant studies, using coping strategies has a significant relationship with well-being . On the Participantsth to 9th grades). The samples consisted of 48 girls and 74 boys, of whom 22 samples (18%) were studying in the 6th grade, 24 samples (19.67%) in the 7th, 51 samples (41.8%) in the 8th and 25 samples (20.5%) in the 9th grades. With no hearing aid, the severity of hearing loss in better ear in 20 subjects (16.4%) was mild, in 85 subjects (69.7%) was moderate and in 17 participants (13.9%) was severe. Using hearing aid, the corrected hearing thresholds in better ear of 83 participants (68%) was within the mild, in 24 subjects (19.7%) was in the moderate and in 15 subjects (12.3%) found in the severe range of hearing loss. Of all participants, 78 cases (51.6%) used hearing aid in one ear, 44 cases (36.1%) in both ears and 8 subjects (6.6%) had cochlear implants. Two students (1.6%) had a parent with hearing loss. About 94 students (77%) had been started to use hearing aids at the ages of 0-4 years and 28 students (23%) from the ages of 5-10 years. In addition, 2 students (1.6%) had cochlear implant when they were 2 years old, 4 students (3.2%) at the age of 3 years and 2 cases (1.6%) at the age of 4 years. The cause of hearing loss for 106 participants (86.89%) was congenital and 16 subjects (13.11%) reported the acquired hearing loss. The study population consisted of 122 students with hearing loss. They were recruited from mainstreaming schools (studying in the 6Instruments1) Demographic questionnaire. A brief demographic questionnaire was used to collect the information, such as gender, grade, using hearing aid and cochlear implant.2) The EPOCH Measure of Adolescent Well-Being. This is a 20-item scale based on the well-being theory and assesses 5 positive psychological characteristics of well-being, including engagement, perseverance, optimism, connectedness and happiness  The Ways of Coping Questionnaire: This is a 66-item questionnaire assessing thoughts and behaviors used by people to deal with stress  in adolescent students with hearing loss. We found no study on EPOCH in this goup; however some studies have addressed other factors associated with poor mental health and psychological well-being of individuals with hearing loss. For example, in a study  YSR Ach in studeFor the second objective, the results of this study showed significant correlations between coping strategies and EPOCH. Although the relationship between overall well-being and using coping strategies has been studied, the researchers have used different measurement tools. Ryff  and KeyeThis study had some limitations. We did not consider some differences, such as differences in oral communication skills of students. The population of people with hearing loss is diverse and they have different needs. Our findings cannot be generalized to all subjects with hearing loss. In Conclusion,The results showed that the present status of positive characteristics of well-being  and coping strategies  among adolescent students with hearing loss. The findings regarding coping strategies and EPOCH can add to the information in this field and also it can be effective for educators and professionals to design interventional programs for adolescents with hearing loss.


A recent article by Le Goic et al.  raises tIn order to establish a vestibular contribution, three conditions need to be fulfilled. Firstly, head angular and/or linear accelerations registered by the semi-circular canal and otolith sensory system, respectively, need to be early enough to contribute to balance corrections observed some 120 ms after the onset of the support surface perturbation –7. SeconBy comparing changes in muscle response amplitudes to translations and rotations of the support surface for bilateral lower leg proprioceptive loss patients , a bilat2 (2) of head AP linear acceleration for 35 cm/s rearward support surface translations despite differences in measurement techniques.The crucial aspect of the above argument for a role for vestibular contributions to balance corrections is the presence of early stimulus evoked head accelerations. Considering only the pitch plane, three types of accelerations are observed; vertical and anterior-posterior linear accelerations and pitch angular accelerations , 8, 14. 2 , 14 whic2 , 16—see 2  and 5 yeLe Goic et al.  did not Hopefully, these measurement issues can be resolved in future studies employing wearable micro-electro-mechanical motion sensors to measure head accelerations. Then, whether or not early head accelerations, which could elicit vestibular-spinal reflexes, are observed for perturbations to stance and gait  should bJA wrote the first draft and contributed to data collection. FH revised the manuscript and contributed to data collection.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.


While morphological traits are often associated with multiple functions, it remains unclear how evolution balances the selective effects of different functions. Birds' beaks function not only in foraging but also in thermoregulating and singing, among other behaviours. Studies of beak evolution abound, however, most focus on a single function. Hence, we quantified relative contributions of different functions over an evolutionary timescale. We measured beak shape using geometric morphometrics and compared this trait with foraging behaviour, climatic variables and song characteristics in a phylogenetic comparative study of an Australasian radiation of songbirds (Meliphagidae). We found that both climate and foraging behaviour were significantly correlated with the beak shape and size. However, foraging ecology had a greater effect on shape, and climate had a nearly equal effect on size. We also found that evolutionary changes in beak morphology had significant consequences for vocal performance: species with elongate-shaped beaks sang at higher frequencies, while species with large beaks sang at a slower pace. The evolution of the avian beak exemplifies how morphological traits can be an evolutionary compromise among functions, and suggests that specialization along any functional axis may increase ecological divergence or reproductive isolation along others. Many studies of adaptation have focused on a single proposed function and measured its effect on trait evolution . HoweverBird beaks are an excellent example of a multifunctional trait. Birds use their beaks for foraging, and selection on beak morphology related to this function is a textbook example of evolution ,7. Howevsplit between elements of beak shape. For example, it is conceivable that selection on foraging behaviour might drive the evolution of relative beak length or depth , but, butsplih (as in ). Alternunctions ,25. Inde [et al.  found th [et al. –29).Aside from functions relating to ecological niche, beaks often also function in visual and acoustic signalling. In songbirds especially, beak size and shape are related to vocal performance . SeveralHoneyeaters are a diverse radiation of songbirds (Passeriformes) that belong to a lineage sister to core oscine lineages, and they have remained almost completely confined to Australasia . Having We used a geometric morphometric approach to quantify the beak shape and size in 101 species of honeyeaters. We integrated this with foraging behaviour from , song ch2.(a)We measured 525 specimens from the Natural History Museum in Tring, UK, to describe variation in beak shape among 101 honeyeater species . We photographed each specimen's beak under standardized focal distance and lighting conditions (Nikon D80 camera with Nikon 105 mm Micro lens). Specimens were aligned relative to the camera using an adjustable stage such that their midsagittal plane was in line with the camera's focal plane, and a measurement standard was included in each photo. We chose a set of four landmarks and 20 semi-landmarks that defined the outline of the rostrum and nare . All langeomorph package in R  of beak shape variation for use in subsequent analyses and visualized their loadings using thin-plate spline warp grids . Procrurp grids . We estiometrics .(b)phytools  and the extent to which they employed comparatively rare, specialized behaviours such as foraging on insect cases and using the beak to lever open rolled substrates .We used data collected as described in  to descrs . The re [et al. . The fir(c)We measured 711 recordings available in public databases at the Macaulay Library at the Cornell Laboratory of Ornithology, the Naturalis Biodiversity Center and the Australian National Wildlife Collection . Our song analysis protocol closely followed those described in previous studies of song evolution ,46. We taven Pro v. 1.5 (Cornell Laboratory of Ornithology 2014) using a window size of 256 samples. On each spectrogram, we recorded the start and end time of the song and each note, as well as the maximum and minimum frequency of each note (for at most 30 notes). From these data, we calculated two metrics of song frequency: mean note minimum frequency and mean note maximum frequency. We also calculated an estimate of ‘song pace’ following [We generated spectrograms in Rollowing , which wollowing ,46 basedollowing ,48–50.(d)R package raster , averagv. 2.6-7 ). Range v. 2.6-7 . Species(e)et al. [Marki et al.  inferredet al. . Their s(f)We performed regression tests to address (i) the relationship between foraging, climate and morphology and (ii) the relationship between morphology and song. In the former set of tests, morphology is the response variable, and in the latter set, song is the response variable. We corrected for similarity owing to shared evolutionary history and included an effect of body size  on beak We employed four sets of comparative analyses: (i) phylogenetic generalized least-squares regressions (PGLS ) were usphylopath (v. 1.0.1 [figure 2a versus b); second, relationships between functions (e.g. between temperature and foraging ecology) either were or were not included (figure 2a versus c). We controlled for the effect of body size on beak size in the path analysis by including the beak size residuals of their allometric regression. We evaluated these models by comparing their C-statistic information criterion (CICc), which describe model fit while taking into account the number of parameters/paths [However, relationships among climate, behaviour and morphology may be complex ,60. Hencv. 1.0.1 ). We tesrs/paths .Figure geomorph function procD.pgls and 5000 iterations of resampling for significance testing. Effect sizes from this analysis are intended to describe the overall contribution of each predictor variable in explaining beak shape evolution in honeyeaters. Pseudo-R2 values were calculated for the beak size as a comparison with beak shape, based on a multivariate phylogenetic regression implemented in phylopath.Because shape is a highly dimensional trait, we also employed several multivariate approaches. We performed (iii) a phylogenetic Procrustes analysis of variance (ANOVA) that treated Procrustes-aligned beak shape as a response variable . In thisWe also performed (iv) a two-block partial least-squares analysis using a matrix of multivariate foraging behaviour traits as a predictor and Procrustes-aligned beak shape as a response variable. This analysis was intended to test for and measure the degree of overall covariation between these highly dimensional traits.3.Acanthorhynchus), whereas high values correspond to short stocky beaks exemplified by miners. Low values of PC2 correspond to straight beaks as in Melithreptus species, whereas high values correspond to highly curved morphologies like those seen in myzomela . We also observed variation in the degree of tapering towards the distal end of the beak . More PC axes were recovered, but none explained greater than 1% of variation.The shape of honeyeater beaks varied among species primarily in their depth and elongation, which was the first PC axis and explained 86% of variation . Beak curvature was similarly correlated with foraging pPCs 1 and 2 such that species foraging for nectar tended to have curved beaks (PGLS: p < 0.05), and species foraging on insect cases  tended to have straight beaks (PGLS: p < 0.001). Species with beaks that tapered at the end tended to forage on or near the ground, whereas species with beaks that tapered throughout tended to forage in the canopy (PGLS: p < 0.01). Because both foraging behaviour and shape are multivariate traits, we also performed a two-block partial least-squares analysis comparing their relationship, which showed a strong correlation between these two character sets .Phylogenetic regressions revealed many relationships among beak morphology, foraging behaviour and climate. In particular, beak depth (PC1) showed significant relationships with foraging pPC1 such that species specializing on nectar had elongated beaks . In the best fitting model, climate and foraging ecology influenced both beak size and beak shape (e). However, foraging ecology had a greater effect on shape and a slightly greater effect on size. Varying the type of body size correction used produced few qualitative changes; winter temperatures had a marginally stronger effect on beak size than foraging when size correction was removed, and both winter temperatures and foraging had marginally reduced effects on beak size when body size was included as a covariate . Examination of the relative variances explained for beak size and multivariate beak shape also showed that, other than allometry, winter temperatures and foraging ecology had the greatest effects on beak size, and foraging ecology had the greatest effect on the beak shape , and species with more elongated beaks exhibited a lower maximum frequency (PGLS: p < 0.01). Species with elongated beaks also sang at a slower pace when correcting for body size instead of beak size . Other characteristics of beak shape, curvature and tapering, showed no significant effects on song characteristics. As expected, species with larger body sizes also exhibited lower minimum frequencies.We found significant relationships between two aspects of beak morphology, size and depth and song characteristics in honeyeaters (4.(a)Our results indicate that the evolution of both beak size and beak shape in honeyeaters was driven by a set of trade-offs among allometry, thermoregulation and foraging ecology. Diet and foraging ecology had a slightly greater effect on beak size than winter temperatures in both types of analyses performed. Previous studies have shown a relationship between climate and beak size ,64 and het al. [Beak shape was correlated with both climate and foraging ecology, but diet in particular explained the most variation in this trait overall . This reet al. , mismatcet al. .et al. [Myzomela sanguinolenta and Anthochaera carunculata) are observed to take nectar from bottle-brush flowers, although they survive by different strategies [Scaling with body size explained a significant amount of variation in beak size, as expected , but thiet al.  reportedet al. , these trategies .(b)We compared the goodness of fit for models including trait–function relationships that were either split (each axis of variation mapped to one function) or shared (each axis of variation mapped to multiple functions). Shared models consistently performed better , suggestThe size of honeyeater species' beaks not only increased in warmer climates but also increased with their reliance on nectar foraging behaviour; beaks also become more elongate under these conditions. This is likely to reflect a set of conflicting selection pressures similar to that observed in studies of granivorous song sparrows ,79, wher(c)Variation in both the beak size and beak shape had a significant effect on song characteristics in honeyeaters . Larger Habitat structure is often implicated as an influence on vocal evolution in birds ,88. The Previous studies uncovered the indirect link between foraging ecology and song performance by examining species known to or expected to vary in the beak size based on their foraging ecology ,14,16,915.Here, we assess the influence of foraging behaviour and climate on the evolution of beak morphology and find that both are correlated with changes in beak size and shape. Indeed, no axis of morphological variation that we examined was associated with an isolated function. The at times conflicting effects of variation in this trait have been observed in wild populations ; here, wOur study confirms others that find relationships between beak size and song evolution ,14,16. O


The global prevalence of sensorineural hearing impairment was first reported by the World Health Organization (WHO) in 1985.–At the individual level, the burden of hearing loss over the life course is substantial and can be exacerbated by negative societal attitudes and prejudice towards affected people. In general, hearing loss has adverse consequences on interpersonal communication, psychosocial well-being, quality of life and economic independence.,,The main drivers for the rising trend in hearing loss include demographic changes attributable to global population growth and improved life expectancy.,,,Since 2007, WHO has promoted increased public awareness of hearing loss through World Hearing Day, held every March. Actions required to curtail the growing number of people with hearing loss and to improve quality of life for those with hearing loss have also been extensively reported.The sustainable development goals explicitly recognize the need for a better quality of life and opportunities for optimal well-being throughout the life course of all people with disability.


At two frequencies, 1 and 4 kHz, there were differences in Chavda types between hearing improvement and no improvement (p < 0.05). Anatomical variances of the AICA loop position did not affect the incidence of ISSNHL or co-morbid symptoms including tinnitus and vertigo. In contrast, comparisons of hearing improvement based on Chavda type classification showed a statistical difference, with a higher proportion of Chavda type 1 showing improvements in hearing (AICA outside IAC).The cerebellopontine angle (CPA) is a triangular-shaped space that lies at the junction of the pons and cerebellum. It contains cranial nerves and the anterior inferior cerebellar artery (AICA). The anatomical shape and location of the AICA is variable within the CPA and internal auditory canal (IAC). A possible etiology of idiopathic sudden sensorineural hearing loss (ISSNHL) is ischemia of the labyrinthine artery, which is a branch of the AICA. As such, the position of the AICA within the CPA and IAC may be related to the clinical development of ISSNHL. We adopted two methods to classify the anatomic position of the AICA, then analyzed whether these classifications affected the clinical features and prognosis of ISSNHL. We retrospectively reviewed patient data from January 2015 to March 2018. Two established classification methods designed by Cahvada and Gorrie et al. were used. Pure tone threshold at four different frequencies , at two different time points , were analyzed. We compared the affected and unaffected ears, and investigated whether there were any differences in hearing recovery and symptoms between the two classification types. There was no difference in AICA types between ears with and without ISSNHL. Patients who had combined symptoms such as tinnitus and vertigo did not show a different AICA distribution compared with patients who did not. There were differences in quantitative hearing improvement between AICA types, although without statistic significance ( The cerebellopontine angle (CPA) is triangular-shaped space filled with cerebrospinal fluid, and is located at the junction of the pons and cerebellum. It contains several crucial structures such as cranial nerves V to VIII, and arteries such as superior cerebellar artery (SCA) and anterior inferior cerebellar artery (AICA). The internal auditory canal (IAC), which is a nerve canal surrounded by bone, rises anterolaterally from the CPA to reach the peripheral cochleovestibular organs. The IAC contains cranial nerves VII and VIII, which are ultimately responsible for facial muscle movement, hearing, and balance .The AICA is a branch of the basilar artery and courses through the CPA posterolaterally to supply the anterior to middle parts of the cerebellum and inferolateral pons. It branches into the labyrinthine artery, which is the sole vascular supply for the labyrinth, cochlea, and vestibular organs. The anatomical shape and location of the AICA is variable in the CPA . In postIdiopathic sudden sensorineural hearing loss (ISSNHL) is a commonly seen disease in the otologic clinic. However, there is no known pathophysiology and current treatment relies on the use of systemic or intra-tympanic steroids. Possible hypotheses include inflammation, labyrinthine artery occlusion, or damage to the cochlear nerve . Given tA number of studies have shown cases of hearing loss with an AICA located within the IAC,  and haveWe retrospectively reviewed patient data from January 2015 to March 2018. This study was approved by the institutional review board of Dankook University Hospital . All patients who were admitted for ISSNHL were enrolled in the study. Verbal informed consents from participants were received. ISSNHL was diagnosed according to traditional criteria, which is defined as a threshold shift of greater than 30 dB in three consecutive frequencies, or if the patient has new hearing loss in a duration less than 3 days . DemograAll MRI test were conducted using a 3 T scanner  with an eight channel head coil. Among the routine IAC MR imaging protocol, 3D T2 VISTA images were selected for analyzing the anatomical configurations of IAC vessel and cranial nerves. Two classification systems were adopted. The first was the Chavda classification published by t-test in cases of a parametric distribution, and Mann–Whitney U test in cases of a nonparametric distribution. Fischer’s exact test was used for the cross-table analysis. A p-value less than 0.05 was considered statistically significant.All data were analyzed by GraphPad Prism  or SPSS  software. A Shapiro–Wilk normality test was used to determine whether the data were parametric or non-parametric. Significant differences between groups were statistically analyzed using p > 0.05, Fisher’s exact test). With regard to the Chavda classification, Chavda type I was the most common, followed by type II, and type III. For the Gorrie classification, the Gorrie type III was the most common .We also analyzed symptoms such as vertigo and tinnitus. The relationship between AICA and symptoms were classified as p = 0.13; 1 kHz: Kruskal–Wallis test, KW statistics = 4.719, p = 0.09; 4 kHz: Kruskal–Wallis test, KW statistics = 4.789, p = 0.09; 8 kHz: Kruskal–Wallis test, KW statistics 3.336, p = 0.19, mean hearing level: Kruskal–Wallis test, KW statistics 3.381, p = 0.18). At lower frequencies , hearing improvements were found in type 2 and type 3 Gorrie configurations. Higher frequencies  did not yield any significant differences in hearing improvements, with a Gorrie type 4 at 4 kHz improving the least. These differences were not statistically significant . According to the classification of Siegel’s criteria, it was found that improved groups, from slight to complete recovery, showed higher Chavda type 1 proportion (>50%) compared to no recovery (Chavda type 1 < 30%) but it failed to reveal statistical significance . As hearing improved across both classifications, all Chavda types had a significant difference at 1 kHz and 4 kHz . There was no statistical significance at other frequencies in Chavda or Gorrie type configurations     and 6.p values between 0.09 and 0.13). At two frequencies, 1 and 4 kHz, there was a difference in Chavda types between patients who experienced hearing improvement and patients who did not. In groups that had improvements in hearing, we found a higher proportion of Chavda type 1 configurations (AICA locating outside the IAC). These results suggest that the anatomic location of the AICA loop may help prognosticate hearing outcomes in ISSNHL patients.In the present study, there were no differences in AICA types in ears with or without ISSNHL. Patients who had combined symptoms such as tinnitus and vertigo did not show a different distribution of AICA type compared to patients without symptoms. This suggests that AICA type does not affect the incidence of ISSNHL and concurrent symptoms. There were some differences in quantitative hearing improvement between types, although without statistical significance  and antiviral agent. In contrast, ischemic attack results in irreversible cochlear damage due to sensorineural cell death,  leading On the other hand, it is possible to argue that in Chavda type 1 response to treatment was better compared to other types. Systemically delivered steroid and antiviral agent could reach the target organ faster in case of lesser complicated anatomical positioning of AICA, such as Chavda type 1, studies comparing outcomes and AICA classifications of the local and systemic treatment would help better understanding considering this point.Anatomical variances in AICA loop position did not affect the incidence of ISSNHL or co-morbid symptoms. In contrast, comparisons between groups with improvements in hearing and those without revealed that a higher proportion of Chavda type 1 (AICA outside IAC) patients had better prognostic outcomes.10.7717/peerj.6582/supp-1File S1Click here for additional data file.


Objective: Hearing loss, one main risk factor of tinnitus and hyperacusis, is believed to involve significant central functional abnormalities. The recruitment of the auditory cortex in non-auditory sensory and higher-order cognitive processing has been demonstrated in the hearing-deprived brain. The dorsolateral prefrontal cortex (dlPFC), which has dense anatomical connections with the auditory pathway, is known to play a crucial role in multi-sensory integration, auditory regulation, and cognitive processing. This study aimed to verify the role of the dlPFC in the cross-modal reorganization and cognitive participation of the auditory cortex in long-term sensorineural hearing loss (SNHL) by combining functional and structural measurements.Methods: Thirty five patients with long-term bilateral SNHL and 35 matched healthy controls underwent structural imaging, resting-state functional magnetic resonance imaging (rs-fMRI), diffusion tensor imaging (DTI), and neuropsychological assessments. Ten SNHL patients were with subjective tinnitus.Results: No differences in gray matter volume, spontaneous neural activity, or diffusion characteristics in the dlPFC were found between the SNHL and control groups. The functional connectivity (FC) between the dlPFC and the auditory cortex and visual areas, such as the cuneus, fusiform, lingual cortex, and calcarine sulcus was increased in patients with SNHL. ANOVA and post hoc tests revealed similar FC alterations in the SNHL patients with and without tinnitus when compared with the normal hearing controls, and SNHL patients with and without tinnitus showed no difference in the dlPFC FC. The FC in the auditory cortex was associated with the symbol digit modality test (SDMT) scores in the SNHL patients, which reflect attentional function, processing speed, and visual working memory. Hearing-related FC with the dlPFC was found in the lingual cortex. A tract-based spatial statistics (TBSS) analysis revealed decreased fractional anisotropy (FA) values, mainly in the temporal inferior fronto-occipital fasciculus (IFOF), which showed remarkable negative correlations with the mean hearing thresholds in SNHL.Conclusion: Higher functional coupling between the dlPFC and auditory and visual areas, accompanied by decreased FA along the IFOF connecting the frontal cortex and the occipito-temporal area, might mediate cross-modal plasticity via top-down regulation and facilitate the involvement of the auditory cortex in higher-order cognitive processing following long-term SNHL. Approximately half a billion people are suffering from disabling hearing deprivation, accounting for 6–8% of the global population . HearingCross-modal plasticity is an intrinsic ability of the central multi-sensory brain, and refers to the recruitment of resources from the deprived modality into the intact sensory processing; it is known as a compensatory adaption of wide-ranging brain circuits . Cross-mApart from low-level sensory processing, accumulating evidence has indicated that the deprived auditory cortex is also recruited for higher-order cognitive functions. Language stimuli-evoked activation in the superior temporal gyrus (STG) of deaf patients shows enhanced functional coupling with frontal areas, which correlates with the language learning function . ActivatThe dorsolateral PFC (dlPFC) plays a crucial role in top-down regulation , multi-sTo verify our hypotheses, we evaluated the structural and functional properties of the dlPFC by combining multimodal magnetic resonance imaging (MRI) techniques. We aimed to determine whether the functional coupling pattern of the dlPFC changes following long-term sensorineural hearing loss (SNHL) with and without accompanying tinnitus, with a particular focus on the multiple sensory areas, and its relevance to hearing perception and higher-order cognitive performance. We further evaluated the properties of the white matter microstructure of the prefrontal-temporal pathway using a tract-based spatial statistics (TBSS) approach. We aimed to identify the dlPFC as a potential biomarker underlying the cross-modal reorganization and cognitive participation of the auditory cortex related to SNHL.Thirty-five patients with long-term bilateral SNHL were recruited for this study . All of these SNHL patients reported consistent hearing loss over the duration from the onset age of 3–42 years. Hearing loss was caused due to a clinical history of ototoxic drug application in one case of the SNHL subjects, others had no clear etiology. Ten of these SNHL patients were accompanied by mild subjective tinnitus. Thirty-five age-, sex-, and education-matched normal-hearing controls were also included in this study . All participants were Chinese Han. The criteria for the inclusion of the patients with long-term bilateral SNHL were as follows: (1) age range: 20–70 years; (2) clinically diagnosed SNHL with a disease duration above 3 years; (3) post-lingual hearing loss; (4) bilateral hearing loss with mean hearing thresholds above 25 dB HL for both ears. The criteria of exclusion for both the SNHL and control groups were as follows: clinically diagnosed Meniere’s disease and acoustic neuroma, a clinical history of head injury, cancer, stroke or otologic surgery, poorly controlled diabetes or hypertension, seizures, Multiple Sclerosis, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, and other neuropsychiatric diseases. This research was approved by the Ethics Committee of Affiliated Zhongda Hospital of Southeast University. A written informed consent was obtained from each of the participants before the experiment. All procedures were performed in accordance with the Declaration of Helsinki.The hearing thresholds were measured at the frequency of 250, 500, 1000, 2000, 4000, and 8000 Hz via pure tone audiometry using a GSI-61 audiometer. The monaural mean hearing threshold was computed as the averaged value of the air conduction thresholds at 500, 1000, 2000, and 4000 Hz. The binaural mean hearing threshold was calculated by averaging the monaural mean hearing thresholds. Acoustic immittance was performed to exclude hearing loss due to conductive deafness. All subjects in the control group had mean thresholds <25 dB HL for both ears. All subjects in the SNHL group had mean thresholds >25 dB for both ears.A series of neuropsychological assessments that covered the relevant cognitive or emotional domains were conducted with all participants. The tests for each participant took approximately 1 h to complete and were administered by the same researcher in the same order. For cognitive assessment, the general cognitive state was evaluated by the Mini Mental State Examination (MMSE) . The funb-values: 0 and 1000 s/mm2, acquired resolution: 2 mm × 2 mm × 2 mm, direction: 30, matrix: 128 × 128.All participants underwent brain structural, resting state fMRI (rs-fMRI), and diffusion tensor imaging (DTI) scanning in a Siemens 3.0 T MRI scanner  with a 12-channel head coil at the Department of Radiology, Affiliated Zhongda Hospital of Southeast University. Soft foam padding was used to alleviate head motion; earplugs and a headphone were used to alleviate the noise during scanning. The participants were instructed to keep their head still, eyes closed, and avoid thinking about anything in particular during the MRI scanning. Structural images were acquired using a high-resolution three-dimensional magnetization-prepared rapid gradient-echo (3D MPRAGE) T1-weighted sequence. The sequence parameters were as follows: repetition time: 1900 ms, echo time: 2.48 ms, flip angle: 9.0°, inversion time: 900 ms, slice number: 176, slice thickness: 1.0 mm, field of view: 250 mm × 250 mm, matrix: 256 × 256. Functional raw data were obtained using a gradient-recalled echo-planar imaging (GRE-EPI) sequence in an interleaved order. The sequence parameters were as follows: repetition time: 1900 ms, echo time: 2.48 ms, flip angle: 90.0°, slice number: 32, slice thickness: 4.0 mm, the field of view: 240 mm × 240 mm, matrix: 64 × 64, volumes number: 240. The DTI raw data were acquired using a single-shot echo planar imaging sequence (EPI) with the following parameters: repetition time: 5800 ms, echo time: 82 ms, flip angle: 90°, slice number: 31, slice thickness: 4.0 mm, p-value threshold <0.05 corrected by the false discovery rate (FDR) method for multiple comparison correction. The region of interest (ROI)-based VBM analysis was used to compare the regional GM volume between two groups. The ROIs were defined from the Brodmann template as the bilateral dlPFC. The subject-specific GM data within the ROI were exacted from the normalized and smoothed GM images.To avoid the impact of structural damage on the functional measurements, we computed the volume of gray matter (GM) and white matter (WM) for each participant using the voxel-based morphometry (VBM) method via the SPM8 toolbox. The T1-weighted images of each subject were segmented into the GM, WM, and cerebro-spinal fluid and then non-linearly normalized to the standard Montreal Neurological Institute (MNI) space. The images after normalization were smoothed with an 8-mm full-width at half-maximum (FWHM) Gaussian kernel. The whole-brain GM and WM volumes were calculated by estimating the segments. The voxel-based between-group difference in GM and WM was determined via analysis of variance (ANOVA) using a general linear model (GLM) with age, sex, and education included as nuisance covariates of no interest. Significant differences were determined to have a 1) and the Data Processing and Analysis for Brain Imaging V2.3 (DPABI2) toolbox were used to preprocess the fMRI data including the following steps: exclusion of the first 10 volumes; slice-timing for correcting the differences in acquisition time between slices; realignment for head motion correction; spatial normalization to a standard template in the MNI space using a DARTAL approach followed by reslicing into 3 mm × 3 mm × 3 mm voxel size; spatial smoothing with a Gaussian kernel size of 6 mm × 6 mm × 6 mm FWHM; linear detrending; nuisance covariate regression for the white matter and cerebrospinal fluid signal and the head motion parameters; bandpass filter with the frequency window from 0.01 to 0.1 Hz. Subjects were excluded if their head motion exceeded 2.0 mm in the x, y, z plane, or 2.0° of axial rotation. No participant was excluded in the current study due to head motion.The Statistical Parametric Mapping software (SPM83). The region of interest (ROI) in the left and right dlPFC was defined using the Wake Forest University (WFU) PickAtlas software4  SNHL patients without tinnitus vs. controls, (2) SNHL patients with tinnitus vs. healthy controls, and (3) SNHL patients without tinnitus vs. SNHL patients with tinnitus. Differences with a p < 0.05/3 were deemed statistically significant for post hoc two-sample t-tests, using an FDR method for multiple comparison correction. A hearing-related FC map was calculated by correlating the binaural mean hearing thresholds with the FC z-scores of each voxel, with the ROI set at the left and right dlPFC, respectively, in all SNHL patients, with age, sex, and education as the covariates. Significant differences were considered with a cluster threshold of p < 0.05 using the Gaussian Random Field method at a voxel height of p < 0.001.The seed-based functional connectivity (FC) analysis was implemented using the Resting-state fMRI Data Analysis Toolkit  was calculated for each participant using the REST software. The preprocessed time series of each voxel was transformed to a power spectrum via a fast-Fourier transform. The square root of the power spectrum was calculated at each frequency and averaged across a low-frequency (0.01–0.1 Hz) domain to acquire the amplitude . Then th5). The skulls were removed using the brain extraction tool of FSL. FMRIB’s Diffusion Toolbox was used to correct head motion and the distortions resulting from the eddy currents, estimate the diffusion tensor, and generate the fractional anisotropy (FA) map and mean diffusion (MD) maps for each participant. Finally, the individual FA and MD maps were directly registered to the high-resolution FMRIB58 template in a 1 mm × 1 mm × 1 mm standard MNI152 space using a non-linear algorithm.The DTI data processing was performed using the FMRIB Software Library .The TBSS analysis was employed following the pipeline of FSL. Briefly, the mean WM tract skeleton was generated in the normalized space with the threshold of FA >0.2, representing the central fiber bundles across all participants. Then all FA maps were projected to the mean FA skeleton. The voxelwise FA values in the WM skeleton were compared between the SNHL group and the control group using a randomization test with 5000 permutations in FSL, with age, sex, and education included as covariates. The statistical significance was set at t-test. Group differences in age, education, and mean hearing thresholds among the SNHL with tinnitus, SNHL without tinnitus and healthy control group were determined with one-way ANOVA. Group difference in sex was determined by the chi-square test . Differences with p < 0.05 were considered to be statistically significant. The correlations between the functional or structural parameters and clinical variants in the SNHL group were assessed using a partial correlation analysis, controlling for age, sex, and education. Differences with p < 0.05 were considered to be statistically significant. To determine the power of the differences observed from the seed-based FC analysis, we used the receiver operating characteristic (ROC) curve analysis and calculated the area under the curve. All data are presented as the mean ± standard deviation (SD).Group differences in age, education, mean hearing thresholds, results of neuropsychological tests, GM volume, ALFF, FA values and MD values in ROIs between SNHL patients and healthy controls were determined with a Student’s p = 0.109). The mean hearing thresholds of both sides in the control group were significantly lower than in the SNHL group and were within the normal range (<20 dB HL). There was no significant difference between the two sides (p = 0.622). Relative to healthy controls, patients with SNHL presented significantly increased SAS and HAM-D scores, and significantly decreased AVLT-5 scores. No other between-group difference was found with regard to the MMSE, AVLT, AVLT-20, or SDMT tests. The detailed demographic, hearing, and neuropsychological results are shown in Thirty five patients with SNHL and 35 healthy controls were included. All of the SNHL subjects had a history of long-term consistent hearing loss when this study was conducted. The mean duration of auditory deprivation in the SNHL subjects was 9.29 ± 8.95 years. Most of them acquired the hearing loss with no clear cause. There was no difference in age, sex, education, handedness, or ethnicity between the SNHL group and control group. The mean hearing thresholds of the left and right side were above 40 dB HL in the SNHL group . There wF = 0.835, p = 0.438), gender  or education . Post hoc Least-Significance Difference (LSD) tests revealed no significant difference in the left mean hearing threshold (p = 0.263), right mean hearing threshold (p = 0.901), or bilateral mean hearing threshold (p = 0.440) between the SNHL patients with tinnitus and SNHL patients without tinnitus.Among the 35 long-term SNHL patients, 10 subjects were accompanied by subjective tinnitus. As illustrated in p < 0.05 corrected by FDR.No significant difference in the GM or WM volumes of the whole brain was observed between the SNHL and control groups at a threshold of As illustrated by The FC patterns of the left and right dlPFC were significantly different between the SNHL and control groups, as presented in To further determine the effect of tinnitus associated with hearing loss on the dlPFC FC changes, we divided the SNHL patients into two subgroups and compared the dlPFC among the SNHL patients without tinnitus, SNHL patients with tinnitus and healthy controls . When thz-scores in the left lingual gyrus were extracted and were found to be positively associated with the binaural mean hearing thresholds  when differentiating patients with SNHL from healthy controls, indicating that the dlPFC might be a potential imaging marker to identify patients with SNHL with cross-modal and higher-order cognitive reorganization in the auditory cortex. In addition, after we divided the SNHL patients into two subgroups according to whether they were accompanied by tinnitus, these two subgroups showed similar FC changes  when compared with the healthy controls, and no between-group difference. These findings indicate that the accompanying tinnitus makes negligible impacts on the hearing loss-related functional reorganization between the dlPFC with auditory, and visual areas. Tinnitus is generally accepted to be associated with the maladaptive plasticity of the auditory deafferentation caused by auditory deprivation . PreviouIt is also important to understand the neural mechanisms underlying such reorganization in the auditory cortex in SNHL and distinguish the structural aspects from the functional aspects. Although the pathological substrates of DTI damage are still not clear, developing quantitative evaluations of the DTI metrics will provide a powerful tool to understand the microstructural features of the WM in the central brain. FA, a DTI measurement of the directional diffusion of water within the WM tracts, depends on the anatomical characteristics of the axonal microstructure . A reducSurprisingly, we found that the functional abnormality of the STG was particularly located in the right side, even though the patients recruited in the current study all had bilateral SNHL. This might be due to the tendency of their higher hearing loss to be on the left side. Another possible explanation might be related to the specification of hemisphere dominance. Phonetic and language processing is left hemisphere dominant in the primary auditory cortex, and pitch processing is right hemisphere dominant in the primary auditory cortex . Prior sSeveral limitations of this study must be acknowledged. First, because of the cross-sectional nature of this study, we were unable to track the dynamic progression of the SNHL. Further longitudinal studies will address this question. Second, although the total pool of subjects in the SNHL and the control groups was more than 30, the sample size was not large enough to divide the patients into different subgroups according to different cognitive or emotional states or by the severity or frequency of characteristics of hearing loss. We were able to partially overcome this problem by performing correlation analyses. Third, the blood-oxygen-level dependent (BOLD) signal is a reflection of local cerebral blood changes and is not a direct measure of neural activity. Combining rs-MRI with other non-invasive techniques, such as electroencephalography or magnetoencephalography, might be helpful to better understand the brain-wise neurophysiological mechanisms underlying SNHL and the cognitive associated with SNHL. Finally, the neuropsychological tests applied in the current study were relatively rudimentary. Future research will address the neural mechanisms underlying the more specific higher-order functions related to SNHL.In summary, the current study substantiated the role of the prefrontal area, particularly the dlPFC, in the recruitment of the auditory area into cross-sensory and higher-order processing through a top-down control in conditions of long-term bilateral SNHL, by providing combined functional and structural neuroimaging evidence. Our findings enhance the understanding of cortical pluripotency and the underlying mechanisms of cross-modal reorganization and cognitive participation in the deprived auditory cortex.YL conducted the experiments, recruited the participants, analyzed the data, and wrote the manuscript. CW helped with the integration of the data. YJ and TT helped with the analyses of the data. JZ helped the data collection. G-JT directed this study, designed the research, and gave key advice.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 subtypes of the morphology term, etiopathogenesis, and the relationship of the candidate BMP4 gene to cross-beaks are not yet known. The objective of this study was to describe the subtypes of cross-beaks by left or right and upper and lower jaw bones and to figure out the relationship between BMP4 and the development of craniofacial bones in Huiyang bearded chickens.Recently, the emergence of cross-beaks has been reported in several domestic chickens. Despite several candidate genes, bone morphogenetic protein 4 (BMP4) and the development of craniofacial bones in Huiyang bearded chickens. We identified five typical subtypes of cross-beaks by morphological assessment and X-ray scanning. We found that cross-beaks caused certain changes in the facial bone morphology, including changes to the length and width of the bone around the ocular area (p < 0.05). The relative expressions of BMP4 in lacrimal, mandible, premaxilla, frontal, and parietal bones were significantly higher in the severe cross-beak group, followed by that of the medium cross-beak group, weak cross-beak group, and control group (p < 0.05). Overall, we constructed a generally applicable method to classify cross-beaks in term of the angle. The skeleton around the ocular area was affected by the cross-beak. The expression levels of BMP4 in craniofacial bones may provide insight to potential role of BMP4 in the development of cross-beaks.Bird beaks are important for biological purposes such as food intake, removing parasites, and defining phenotypic attributes. Cross-beaks are a threat to poultry health and are harmful to productivity, wasting some units in the poultry industry. However, there is still limited research on subtypes of cross-beaks and the genetic basis of cross-beaks as well. Here, we described the subtypes of cross-beaks in terms of left or right and upper or lower jaw bones. We evaluated the impact of cross-beaks on craniofacial bones and figured out the relationship between  A cross-beak is a dysmorphology relating to deformed beaks and has been suggested as a threat to animal welfare breeding. There are 1%–3% of Chinese native chickens that have beak deformities, leading to great economic loss and animal welfare issues in the poultry industry ,3. TypicCross-beaks have been identified as four different types by Landauer . The firbone morphogenetic protein gene family (BMP), related to cross-beaks have been proposed in chickens [BMP gene family and TGF-beta superfamily, bone morphogenetic protein 4 (BMP4) is involved in several processes of skeletal development, such as cranio-maxillofacial bone formation [BMP4 plays a critical role in craniofacial traits [BMP4 might serve in beak development, but the authors did not mention the relationship of BMP4 with cross-beaks [BMP4 is involved in the development of cross-beaks is not yet known.Various factors including trauma, abrasion of the rhamphotheca, exposure to toxins ,6, nutrichickens ,9,10. Asormation ,12, and ormation ,14. Prevl traits ,15,16. FBMP4 in craniofacial bones of cross-beaks with different crossed angles. We aimed to provide insights into the underlying genetic mechanism of BMP4 in craniofacial bones in the development of chicken cross-beaks. In this study, we first constructed the nomenclature of cross-beaks by the left or right and upper or lower deflection of the jaw bones, then we defined the morphology and graded the angle of the cross-beak. Afterward, we determined the expression levels of The study was approved by the Animal Care Committee of Foshan University . All animal experiments were performed according to national and international guidelines for animal welfare. A total of 259 out of 6276 chickens, including 150 abnormal chickens as case group and 109 normal chickens as control group, were selected for the study. All chickens were collected from one pure line of Huiyang bearded chickens and fed with corn–soybean-type diets at Foshan University.All chickens that were characterized as having a cross-beak, by one or both beaks deviating laterally from the longitudinal axis of the head along with the backbone, were selected according to a previous study . The maiAll experimental chickens of 105 d of age were slaughtered by rapid decapitation. Afterwards, the deviated angle of a cross-beak was immediately measured by a protractor before necropsy. We defined three cross-beak groups in terms of their deviated angles. The angles of weak, medium, and severe cross-beak chickens were 1°–10°, 10°–20°, and ≥20°, respectively.The distance of the left/right eye midpoint to the upper beak (DLU/DRU), the length of left/right ocular (LOL/ROL) and width of the left/right ocular (LOW/ROW), and that of the left/right eye midpoint to the nostril (DLN/DRN) were determined with a Vernier caliper. Thereafter, the infraorbital sinus was exposed by cutting along the yellow dotted line . The len18 were mixed at 70 °C for denaturation and immediately placed on ice for 5 min. Then, 7.5 μL of ddH2O, 4 μL of Reverse Transcription 5× Buffer, 2 μL of dNTPs (10 mM), 0.5 μL of Recombinant RNasin® Ribonuclease Inhibitor, and 1 μL of M-MLV Reverse Transcriptase were added in each 20 μL Reverse Transcription reaction system. After being fully mixed, they underwent reverse transcription at 42 °C for 1 h and finally inactivated to reverse transcriptase at 72 °C for 10 min. The cDNA was stored at −80 °C for subsequent qRT-PCR.When slaughtered and dissected, the tissues of lacrimal, turbinate, premaxilla, nasal, mandible, parietal, frontal, and occipital bones were independently collected from six female chickens in each group . The samples were immediately frozen in liquid nitrogen and then stored at −80 °C until RNA isolation. The bone tissues were placed in a beaded tube  with Trizol reagent . FastPrep-24™5G  was used to agitate the sample tube at a speed of 5 m/s for 35 s. Then, samples were centrifuged at 12,000 rpm for 15 min at 4 °C, and the upper aqueous layer was transferred to a new tube for the next RNA extraction. The residual gDNA and protein were removed with Dnase I  and RNA clean kit . The purified RNA was dissolved  and stored at −80 °C. After that, 2 μL of total RNA and 3 μL of Oligo(dT)BMP4 in different skull parts using the ABI 7500 Realtime Detection System  and RT-PCR reagents . Each 20 μL PCR reaction system contained 10 μL of 2 × TransStart Top/Tip Green Qpce, 0.4 μL (10 pM) of each primer, 0.4 μL of Passive Reference Dye (50×), 0.8 μL of cDNA (100 ng), and 8 μL of ddH2O. After an initial denaturing for 30 s at 95 °C, there were 40 cycles of amplification , followed by thermal denaturing to generate melting curves. GAPDH was amplified in the same plates as endogenous controls. Samples were assayed in triplicate for standard curves. PCR efficiency, amplification efficiency of the transcripts of interest, and the internal standard of GAPDH were consistent with the measurement of BMP4. Dissociation curves verified that amplification was specific. Relative quantitative expression of the target gene was calculated using the 2−ΔΔCt method [BMP4 and GAPDH are shown in Then, qRT-PCR was performed to determine the expression of t method . The pri2. Significance tests were analyzed using Duncan’s multiple range test, and the effects and differences were considered statistically significant when p < 0.05.The data for angle, distance, and gene expression were expressed as mean ± standard deviation (M ± SD). We first analyzed the difference of gender (proportion) among left-crossed chickens, right-crossed chickens, and normal chickens by using chi square tests. Since the gender did not affect the type of crossed beak, we then analyzed the difference (proportion) of left-upper cross-beak, left-lower cross-beak, right-upper cross-beak, right-lower cross-beak, and polarization cross-beak chickens as well as the upper cross-beak and lower cross-beak chickens regardless of gender by a chi square test. Data of gene expression and distance were checked for normality and homogeneity of variance and were transformed where necessary. Samples for gene expression were selected for female chickens, which were analyzed using one-way  analysis of variance (ANOVA) by SPSS 20.0. While, data of distance were analyzed using two-way analysis of variance (ANOVA) by SPSS 20.0. The gender and treatment  as factors were included in the model. Yijk = μ + Ai + Bj + (AB)ij + εijk, where Yijk is observation k (angles/distances) at the level i type of beak (TOB) and the level j gender (G), μ is the overall mean, Ai is the effect of level i type of beak, Bj is the effect of level j gender, (AB)ij is the effect of the interaction of level i TOB with level j G, and εijk is the random error with mean 0 and variance σp < 0.05). Meanwhile, lower cross-beaks (54.67%) occurred more frequently than upper cross-beaks (31.33%) (p < 0.05).Referring to the above nomenclature, there were five subtypes of cross-beaks versus the normal beaks A. They wThe average angle of left cross-beaks was 9.86° . Among tp < 0.01, p < 0.05), but not in RC and NC chickens  and G (p < 0.01) (p < 0.01). Besides, the LOL in female chickens with left/right cross-beaks was shorter than male chickens with left/right cross-beaks (p < 0.01). The ROL was affected by the TOB (p < 0.01) and G (p < 0.05) (p < 0.01). Furthermore, that distance in female chickens with left/right cross-beaks was shorter than male chickens with left/right cross-beaks (p < 0.05). The LOW and ROW were affected by TOB, with short values in chickens with left/right cross-beaks than normal chickens  (p < 0.01). The LIS and RIS were affected by TOB (p < 0.01) (p < 0.01). The LIS was longer in left cross-beaks than normal chickens and right crossed beak chickens (p < 0.01).The gender and the interaction of gender × TOB showed no effects on DLU A, DRU FB, DRN FD, LOW FG, ROW FH, LIS FI, and RIchickens C. The DR < 0.01) E, showin < 0.05) F, with a < 0.01) H. In chi < 0.01) I,J. The BMP4 in mandible, premaxilla, lacrimal, frontal, and parietal bones were significantly higher in the severe cross-beak group, followed by that of the medium cross-beak group, weak cross-beak group, and control group (p < 0.01) (The relative expressions of  < 0.01) A. But th < 0.01) B.Cross-beaks are a disease resulting in economic loss for the poultry industry and comprise 1% to 3% in Chinese local chickens . A beak Since severe cross-beaks influence food and water intake and survival, some chickens may not grow to the adult age. Thus, it makes sense that weak cross-beak chickens show greater proportions among the chicken population with deformed beaks. We did not find that the upper and lower beaks deflected to the same direction simultaneously, regardless of what was previously reported . In crosBMP4 is a critical gene for the development of the beak [BMP4 with cross-beaks. Its expression in multiple craniofacial bones suggested that BMP4 might be involved in the regulation of multiple craniofacial bone growth and development pathways in chickens, such as the development of lacrimal, mandible and the premaxilla, parietal, and frontal bones. Previous studies indicated that overdosed BMP activities were also detrimental to multiple axial skeletal tissues and facial skeletal formation [BMP4 signaling caused decreased proliferation, reduced retinal volume, and altered the shape of the optic cup [BMP4, with malformations of the skull bone, tissues, and organs, is species-specific. For example, in blind cave-dwelling fish, BMP4 was associated with asymmetric craniofacial development [BMP signals disrupted the normal development of the palate and teeth [BMP4 is related to the malformation of tissues and organs, such as dysplasia of the lumbosacral spinal cord in rats [BMP4 in lymphocytes, which suggests that an inappropriate enhancement of BMP4 expression may play an essential role in the molecular pathophysiology of fibrodysplasia ossificans progressiva [BMP4 might be linked to alternations in parietal, frontal, lacrimal, mandible, and premaxilla bones, but not in turbinate, nasal, and occipital bones. Intriguingly, the level of BMP4 along the entire dorso-ventral axis of the optic cup suggests that the activity of BMP4 is not limited by distance [BMP4 in bones at a certain distance from the beak is the cause of the occurrence of cross-beaks.Although most of the cross-beak lesions were observed to change in the upper and lower jawbones, our morphological results indicate that the occurrence of deformed beaks is likely related to the malformed development of craniofacial bones. The external differences in beak morphology reflect differences in their respective craniofacial skeletons . Thus, cthe beak ,27. Our ormation ,27,28. Iptic cup . Moreoveelopment . In humand teeth ,32. Othe in rats , in mult in rats ,35, and  in rats . Furthergressiva ,38. Specdistance . It seemBMP4 was the highest in the severe cross-beak chickens, as expected, and followed by medium cross-beak chickens, weak cross-beak chickens, and normal-beak chickens in sequence. This finding was identical to the previous report, that an increase in the deviation angle of the beak was accompanied with an increase in BMP4 administration, and could induce the phenotype similar to that of beak deformity [BMP4, for instance, the injection of exogenous BMP4 into the neural crest-derived interstitium resulting in an increase in width and depth of the beak [In this study, the relative expression of eformity . Noteworthe beak .BMP signaling results in dramatic apoptosis in cranial neural crest (CNC) cells and their derivatives [In addition, overdosed ivatives ,40,41. Livatives ,43. The ivatives . Besidesivatives . These pBMP4 in parietal, frontal, lacrimal, mandible, and premaxilla bones result in cross-beaks, but not in turbinate, nasal, and occipital bones. This finding provides insight on the potential role of BMP4 in the development of cross-beaks. There are five subtypes of cross-beaks in Huiyang bearded chicken. The skeleton around the ocular area is affected by a cross-beak. The over-expressions of


CD59 cause CIDP-like polyneuropathy in children with inherited chronic hemolysis. We hypothesized that mutations in CD59 might be found in a subset of sporadic CIDP patients.Mutations in CD59 coding region was amplified by PCR and Sanger sequenced.35 patients from two centers, fulfilling the EFNS/PNS diagnostic criteria for CIDP were included. One rare variant was detected in a patient which resulted in a synonymous change and predicted to be neutral. Pathogenic variants were absent in our cohort.CD59 are absent in adult-onset sporadic CIDP.Our pilot study suggests that mutations in  Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare and heterogeneous neurological disorder that is diagnosed according to clinical and electrophysiological diagnostic criteria. Its pathogenesis is largely unknown although an autoimmune origin is widely accepted. The response to immunomodulatory therapy, including intravenous immunoglobulins (IVIg), glucocorticosteroids and plasma exchange, supports the autoimmune hypothesis and the role of humoral factors, including autoantibodies, in its pathogenesis. Traditional CIDP pathogenic models describe the presence of combined cell-mediated and humoral immunity that result in an aberrant immune response targeting myelinated fibres of peripheral nerves . HoweverCD59, a complement inhibitor present in the surface of red blood cells, was discovered in five Jewish children from North-Africa with chronic haemolysis and childhood relapsing immune-mediated polyneuropathy[A non-synonymous homozygous mutation (p.Cys58Tyr) in de novo mutations in CD59 might account for a fraction of adult-onset sporadic CIDP patients. With the aim of evaluating the possible role of CD59 in CIDP, its coding region was fully sequenced in a homogeneous series of patients who did not present detectable anti-NF155, anti-contactin-1, NF140/186 or CASPR1 autoantibodies.We then hypothesized that Patients diagnosed with CIDP according to the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) diagnostic criteria providedCD59 gene (transcript variant CD59-211 ENST00000642928.1) was amplified by polymerase chain reaction (PCR) and Sanger sequenced on an ABI 3100 automatic sequencer .The entire coding region of In silico evaluation of potential deleterious effects of CD59 genetic variants was performed with the CADD-score (http://cadd.gs.washington.edu/), Mutation Taster (http://www.mutationtaster.org/), SIFT (http://sift.jcvi.org/), and Human Splicing Finder tool (http://www.umd.be/HSF3/index.html).Resulting electropherograms were visually analyzed using Sequencher software . Primer pair sequences and PCR conditions are available under request. CD59 was performed. Only one variant was detected in one patient (http://gnomad.broadinstitute.org/) this is a rare variant with an allele frequency of 0.003 in ExAC database and 0.001899 in gnomAD database in non-Finnish Europeans. In silico analysis of possible damaging consequences did not reveal any potential deleterious effect related to this genetic variant. The previously reported pathogenic p.Cys58Tyr mutation was not present in our patient cohort.A total of 35 patients  were included in the study. Direct sequencing of all coding exons of  patient , a heterOur pilot study failed to identify functionally-relevant CD59 mutations in sporadic adult-onset CIDP patients suggesting that genetic dysfunction of CD59 is not a frequent cause of CIDP. A rare variant was found in one patient but was predicted to be functionally irrelevant.CD59 (protectin) encodes a glycosylphosphatidylinositol (GPI)-anchored cell surface membrane glycoprotein, which inhibits polymerization of complement molecule C9, the final step of membrane attack complex (MAC) formation, to protect host cells from complement-mediated lysis [CD59 thus might make cells, such as Schwann cells, susceptible to MAC-mediated lysis, possibly causing demyelination. In fact, complement deposits have been observed in areas of demyelination in sural nerve biopsies of patients with CIDP [CD59-deficient mice show MAC deposits in the perivascular tissue in the areas of demyelination, and are more susceptible to experimental autoimmune encephalomyelitis, inflammation and axonal loss than wild type mice [Loss of function of ith CIDP ,12. Alsoype mice .CD59 deficiency is an extremely rare and recently described disease characterized by hemolysis, recurrent ischemic strokes and relapsing immune-mediated polyneuropathy [Congenital uropathy .CD59 mutation p.Cys58Tyr[CD59 mutations have been described. In 2015, a homozygous missense mutation  was reported to be pathogenic in three Turkish patients from a two-generation family with immune-mediated peripheral neuropathy, chronic hemolysis and strokes [CD59  has been described in a 7-year-old girl with a demyelinating polyneuropathy and cerebral vasculopathy [After the description of the pathogenic CD59 as an essential complement regulatory protein for protection of hematopoietic and Schwann cells against complement attack.These severe symptoms support the importance of CD59 deficiency is well known in paroxysmal nocturnal hemoglobinuria (PNH), where a clonal defect in GPI biosynthesis confined to the hematological system, results in hemolysis and prothrombotic tendency[Acquired  tendency. Eculizu tendency. Therefo tendency. DetectiCD59 alterations in CIDP. However, a study investigated the presence of antibodies targeting the complement inhibitors CD46, CD55 and CD59 and found no association of these antibodies with inflammatory neuropathies [To our knowledge, this is the first genetic study aimed at identifying opathies .In summary, our results suggest that CD59 mutations are not present in sporadic CIDP patients. We did not study somatic mutations restricted to nerve (mosaicism) or to regulatory regions of CD59 and, thus, the possibility that CD59 dysfunction plays a role in some CIDP patients has not been completely ruled out. Caution should be made in interpreting our data, since we used a limited series of patients and, therefore, we cannot exclude that rare CD59 mutations are the cause of sporadic CIDP. However, our study suggests that these mutations are not a frequent cause of CIDP. Since CIDP is a very rare disease and single-center case series are consequently small, further genetic and immunologic studies in larger, collaborative, CIDP cohorts  are needLQ has provided expert testimony for Grifols, Genzyme and CSL Behring, received speaking honoraria from Biogen Spain and Roche and received research funds from Grifols (Spin Award) and LFB. This does not alter our adherence to PLOS ONE policies on sharing data and materials.