To investigate the relationship between the retinal thickness in different subfields and the volume of white matter hyperintensity (WMH), with the hope to provide new evidence for the potential association between the retina and the brain.A total of 185 participants aged over 40 years were included in our study. Magnetic resonance imaging (MRI) was used to image the WMH, and WMH volume was quantitatively measured by a specific toolbox. The thickness of the total retina, the retinal nerve fiber layer (RNFL), and the ganglion cell and inner plexiform layer (GCIP) was measured by optical coherence tomography (OCT) in nine subfields. The association between retinal thickness and WMH volume was demonstrated using binary logistic regression and Pearson correlation analysis.P for trend = 0.044)/ GCIP  at the central fovea, and a negative linear trend correlation with the thickness of nasal inner RNFL , nasal outer RNFL , and inferior outer RNFL , after adjusting for possible confounders. Correlation analysis results showed that WMH volume had a significant negative correlation with superior outer RNFL thickness  and nasal outer RNFL thickness .Participants were divided into two groups by the WMH volume  median. In the quartile-stratified binary logistic regression analysis, we found that the risk of higher WMH volume showed a positive linear trend correlation with the thickness of total retina (95% CI: 0.848 to 7.034; It is suggested that central fovea and outer retina thickness are respectively associated with WMH volume. OCT may be a biological marker for early detection and longitudinal monitoring of WMH. White matter hyperintensity (WMH) is a manifestation of cerebral small vessel disease. It is divided into periventricular white matter hyperintensity (PWMH) and deep white matter hyperintensity (DWMH) according to the location. Its pathology remains unknown. Current studies suggest that it is related to white matter (WM) demyelination, axon loss, and gliosis caused by blood–brain barrier leakage, hypoperfusion, vessel endothelial dysfunction, inflammatory response, oxidative stress, and venous drainage disturbance –5. DWMH in vivo. OCT system generates cross-sectional images of the retina that show the reflectivity information captured in depth by means of whiter or darker bands , ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer, outer plexiform layer, outer nuclear layer, external limiting membrane, and photoreceptor segments] and retinal pigment epithelial layer . Opticaler bands . RNFL iser bands . The macer bands . In the er bands .The retina is regarded to be an extension of the brain. They have the same properties in embryology, physiology, and morphology. First, the retina develops from the diencephalon during the embryonic stage . Next, gOptical coherence tomography has been used to explore some cerebral diseases, like Alzheimer's disease (AD), multiple sclerosis, Parkinson's disease, and neuromyelitis optical spectrum disorder –18. A prin vivo. Recent studies have demonstrated the association between WMH and retinal vessel diameter  neurological diseases, such as acute and large-area stroke, tumor, epilepsy, mental disorders, central nervous system demyelinating disease, or trauma; (2) any cognitive deterioration history or ever had a diagnosis of dementia; (3) Barthel Activities of Daily Living Index  < 80 ; (4) conA number of variables, including age, gender, body mass index (BMI), medical history , current smoking, alcohol use, systolic blood pressure (SBP), and diastolic blood pressure (DBP), were collected. We recorded laboratory indicators, including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), fasting plasma glucose (FPG), and uric acid (UA).All eligible participants underwent 3.0 tesla MR scanners   with a slice thickness of 5 mm. WMH is the high signal area on T2-weighted and FLAIR .The WMH was visually evaluated on FLAIR based on the Fazekas scale by an experienced neuro-radiologist. PWMH is WMH contiguous with the margins of each lateral ventricle, while DWMH is WMH separate from the ventricles . PWMH schttp://dbm.neuro.uni-jena.de/cat/) established on SPM12  in Matlab   . Images ks, USA) . A GaussThe WMH volume was segmented by the Lesion Growth Algorithm (LGA) from the LST toolbox  . This toStandardized WMH volume = actual WMH volume/ total intracranial volume . WMH volRetinal images were taken for all subjects by the OCT imaging system. The Swept Source OCT  with 3D scans  was used to obtain OCT scans centered at the fovea. The scans were obtained without pharmacological mydriasis under dark room conditions. All the OCT scans were reviewed by an experienced ophthalmologist to exclude poor-quality OCT scans. We excluded OCT scans of poor quality according to the OSCAR-IB criteria . The OCTT-tests or Mann–Whitney U-tests were used for continuous variables, and χ2-tests were used for categorical variables. The thickness of the retina was analyzed by the T-tests. The pattern diagrams of ETDRS grids were drawn to display the changes in retina thickness more vividly  was used for all analyses, with a P-value of < 0.05 as the significance level.Continuous variables were presented as mean ± standard deviation or median (interquartile range) as appropriate. Categorical variables were presented as frequencies and percentages. The  vividly . Thicken vividly . The assWe included 185 participants in this research. The participants were divided into two groups by the WMH volume  median. A total of 92 participants were grouped as the lower WMH volume group , and 93 participants were grouped as the higher WMH volume group .The characteristics of participants in the lower WMH volume group and the higher WMH volume group are summarized in P = 0.016), and thinner superior inner total retina (P < 0.001)/ RNFL (P = 0.034)/ GCIP (P = 0.014), nasal inner total retina (P = 0.006)/ RNFL (P = 0.039)/ GCIP (P = 0.027), inferior inner total retina (P = 0.007)/ GCIP (P = 0.018), temporal inner total retina (P = 0.017)/ GCIP (P = 0.033), superior outer total retina (P = 0.001)/ RNFL (P = 0.007) /GCIP (P = 0.006), nasal outer total retina (P < 0.001)/ RNFL (P < 0.001), inferior outer total retina (P = 0.003)/ RNFL (P = 0.001), and temporal outer total retina (P = 0.006)/ GCIP (P = 0.004) thickness, when compared to the participants with lower WMH volume (P = 0.146)/ GCIP (P = 0.078) at the central fovea, inferior inner RNFL (P = 0.196), temporal inner RNFL (P = 0.972), nasal outer GCIP (P = 0.085), inferior outer GCIP (P = 0.105), and temporal outer RNFL (P = 0.188) when both groups were compared / GCIP  at the central fovea, and thinner nasal inner RNFL , nasal outer RNFL , inferior outer RNFL , and temporal outer GCIP  were associated with an increase in the risk of higher WMH volume, after adjusting for age, gender, hypertension, CHD, stroke, SBP, and LDL-C (P for trend = 0.044) for total retina thickness at the central fovea, 3.65  for GCIP thickness at the central fovea, 0.26  for nasal inner RNFL thickness, 0.181  for nasal outer RNFL thickness, and 0.232  for inferior outer RNFL thickness, after adjusting for age, gender, hypertension, CHD, stroke, SBP, and LDL-C. The correlation analysis results showed that WMH volume had a significantly negative correlation with superior outer RNFL thickness  and nasal outer RNFL thickness / RNFL  at the central fovea and thinner nasal outer RNFL  were associated with an increase in the risk of moderate-severe PWMH, while thinner superior outer RNFL , nasal outer RNFL , inferior outer RNFL , and temporal outer GCIP  were associated with an increase in the risk of moderate-severe DWMH, after adjusting for age, gender, hypertension, CHD, stroke, SBP, and LDL-C (We divided the participants into the mild group (Fazekas 0–1) and the moderate-severe group (Fazekas 2–3) according to the PWMH score and DWMH score, respectively. In binary logistic regression, thicker total retina  leading to reduced blood flow, tissue ischemia, and hypoxia could also cause retinal changes and ultimately affect vision, which is similar to the pathological mechanism of WMH , 44. OCTIn this study, WMH volume had a significant negative correlation with superior outer and nasal outer RNFL thickness, rather than in the other quadrants. The precise cause of the area difference in RNFL thickness reduction is unknown at this time. It might be due to the special direction of the nerve fibers in the macula. Nerve fibers in the nasal quadrant arrive at the optic disk directly. Nerve fibers in the temporal quadrant are bounded by horizontal meridians, which, respectively, curve around the macular fovea and reach the optic disk . Among hZ-shape” trajectory to extend around . Studies found that Aβ deposits may occur in the retina, even before the deposits in the brain . BernardSimilar observations have documented that the thinning of RNFL was related to the degree of WMH , 34, 62.Retinal thickness changes are in many cases compensatory among subfields and sublayers. It is closely related to the measuring method. A previous study found that geometrically predetermined regions  might cause thickening and thinning within the same region to cancel each other out and lead to the clinically relevant differences being masked. In contrast, the color-coded quantitative maps could allow point-to-point comparisons between groups and provide more precise regions of change . MoreoveThere are several limitations to our study. First, retrospective studies can just investigate the associations. Prospective studies are necessary to demonstrate our results. Second, the sample capacity of this study is restricted. The hypothesis must be validated in a large study. Third, we did not measure the thickness of other retinal sublayers separately and RNFL in the peripapillary area, so we cannot explore their relationship with WMH and the compensatory among sublayers. Complementary studies where each retinal layer is studied separately, as well as the RNFL in the peripapillary area, are needed. Furthermore, PWMH and DWMH have different mechanisms, but the LST toolbox cannot distinguish between them. More sophisticated software is needed to measure WMH volume in different regions. Furthermore, we did not measure the thickness of the outer retinal sublayers separately, so we cannot explore the relationship between outer retinal sublayers and WMH. Further large prospective studies with more exact instruments to prove the longitudinal association between all retinal sublayers thickness and WMH are required to solve these problems.In conclusion, we found that the increase in the risk of higher WMH volume was associated with the thickening of total retina and GCIP at the central fovea, and the thinning of nasal inner, nasal outer, and inferior outer RNFL. WMH volume had a significant negative correlation with superior outer and nasal outer RNFL thickness. DWMH was more correlated with the thinning of outer RNFL, while PWMH was more correlated with the thickening of the retina at the central fovea. This study provides new evidence for the potential retina–brain association. OCT, as a non-invasive, reproducible, affordable, and convenient technique, may prove to be a biological marker for the early detection and longitudinal monitoring of WMH. Additionally, dynamic observation of retinal thickness changes could also be used to studies on the mechanism of some brain-related diseases. To fully elucidate the relationship between retinal thickness and WMH, further longitudinal and randomized studies with larger sample capacity are needed.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethical Committee of Hebei General Hospital . Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. Written informed consent was not obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.PL proposed the conception of the study and revised the manuscript. XL performed the data acquisition and wrote the manuscript. ZT contributed to the analysis and interpretation of data. ZJ, YD, and JX offered clinical suggestions and performed the data validation. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Cuttlefish is an important species both in scientific and commercial use. To improve their welfare, assessments and reducing pain in animals are necessary. However, studies on nociception in cephalopods have so far focused on the octopus and squid, with no investigations with respect to our knowledge on cuttlefish. We used acetic acid to identify grooming, a key behaviour linked to pain in cuttlefish, as the assessment of pain and ascertained the efficacy of analgesics on pain perception in cuttlefish. We found that when more acetic acid is injected, increased grooming behaviour is induced in cuttlefish, and the injection of lidocaine reduced grooming behaviours in acetic-acid-injected cuttlefish; thus, we can recommend this drug for use as a local anesthetic.Nociception is the neural process of encoding noxious stimuli and is typically accompanied by a reflex withdrawal response away from the potentially injurious stimulus. Studies on nociception in cephalopods have so far focused on octopus and squid, with no investigations to our knowledge on cuttlefish. Yet, these are an important species both in scientific and commercial use. Therefore, the present study demonstrated that a standard pain stimulus, acetic acid, induced grooming behaviour directed towards the injection site in cuttlefish and that the injection of lidocaine reduces grooming behaviours in acetic-acid-injected cuttlefish. Wound-directed behaviour demonstrates that the animal is aware of the damage; thus, when subjecting these animals to any painful treatments in the laboratory, researchers should consider alleviating pain by the administration of pain-relieving drugs. Nociception is the neural process of encoding noxious stimuli and is typically accompanied by a reflex withdrawal response away from the potentially injurious stimulus . If damaThe cephalopods , which have the most complex central nervous systems among invertebrates ,9, are pThis study was conducted with ethics approval from the Institutional Animal Care and Use Committee of the National Tsing Hua University (protocol no. 111025).Sepia pharaonis), which were spawned by wild caught females, were incubated by the Aquatic Biotech Company Ltd.  during March 2021 for 2 weeks. The eggs were then transported to the aquarium at the National Tsing Hua University . After hatching, juvenile cuttlefish were housed individually in porous containers floating inside the rearing tank. Depending on the individual cuttlefish’s mantle length (ML), different containers were used . Cuttlefish are solitary individuals and show aggression to conspecifics; therefore, individual housing prevented any aggression. The animals were fed two post-larval white shrimp (Litopenaeus vannamei) and freshwater shrimp (Neocaridina denticulate) twice per day. The length of the shrimp was about 50% of the cuttlefish’s body length. In total 35 cuttlefish were used in the present study. After experiments concluded, animals were returned to their home tank and remained in the laboratory that was kept in optimal conditions. As they were unfit to return to the wild, they were held until they died of natural causes. Their typical lifespan is 240 days, so they lived for a natural length of time in the laboratory’s aquarium.The eggs of pharaoh cuttlefish  that were maintained at approximately 24°C, with seawater taken from the ocean at a salinity of 33 parts per thousand. Seawater in the rearing tank passed through a mechanical and biological filter with a protein skimmer (removes organic compounds), coral sand (as a bio-filter), and UV light (to kill any microorganisms present). An airstone linked to an aquarium air pump via an airline in the filter tank was used to oxygenate the seawater. The photoperiod of the recirculating aquaculture systems was a 12/12 h light/dark cycle. Water quality is assessed by measuring pH, ammonia, nitrite, and nitrate levels daily using a pH meter and commercially available water-testing kits (API). The average pH of the seawater was 8.0 ± 0.5. The amount of ammonia and nitrite was kept under 0.25 ppm, and the amount of nitrate was under 80 ppm. To ensure acceptable water quality, 20% of the water volume in each tank was replaced weekly.For the experimental setup, aluminium extrusion frames were used to fix the position of the camera and the LED lights see . A digitCuttlefish were removed from their home tank and placed immediately into 1% or 1.5% ethanol in seawater for 5 min for anesthesia. Depending on the individual cuttlefish’s ML, different concentrations of ethanol were used . Then, the cuttlefish were injected subcutaneously on the fourth right arm with either sterile seawater (control) or acetic acid (pain) with a Hamilton syringe. The length of time for anesthesia and injection was less than 10 min. Cuttlefish were then immediately moved into the acrylic recording tank with only seawater and the recording of their behaviour for 10 min started with the camera when they were fully awake.Cuttlefish (N = 41) were randomly assigned to one of the following experimental groups.v/v (5 mL/L) acetic acid was used since this induces lasting, location-specific grooming in octopus [An injection of 0.5%  octopus . To invew/v (5 g/L) of injected lidocaine has been shown to be effective in preventing responses to a pinch in cuttlefish [Local anesthesia using 0.5% ttlefish . To inveTo control for any negative effects caused by lidocaine , 3% LidoTo control for any pain caused by injection, 2 μL of sterile seawater rather than acetic acid was injected subcutaneously into the cuttlefish’s arm N = 6, .To control for changes in the cuttlefish’s behaviour due to handling and anesthesia, cuttlefish (N = 5) were anesthetized with no injection and then immediately moved into the acrylic recording tank .p < 0.001), the total grooming time for different treatments were compared using the Kruskal–Wallis test to analyse whether time spent on grooming differed between treatment groups. Since we were only interested in the impact of lidocaine on grooming behaviour caused by acetic acid, we performed planned comparisons after the Kruskal–Wallis test using Mann–Whitney U tests for only 6 comparisons, with Bonferroni corrections applied. All statistics were conducted using SPSS Version 20.0.0.For each cuttlefish, the behavioural scoring of pain-related behaviour (grooming) was conducted for all recording videos using direct observation. Grooming was defined as the cuttlefish touching the injection site with its other arms. The total time period in which the cuttlefish showed grooming behaviour was calculated. For the intra-observer reliability test, the same observer randomly selected 6 videos and repeated the measurements of grooming time on a separate day from the first observation. The intraclass correlation (ICC) was used to determine the intra-observer reliability. The result suggested that the intra-observer reliability for grooming time was valid (ICC = 0.996). Due to the data not being normally distributed . Grooming behaviour did not occur in the sham control group (p = 0.024). The cuttlefish injected with 2% acetic acid showed even more grooming behaviour than the sham control (p = 0.024) and 0.5% acetic acid groups (p = 0.012).There was a significant difference in the time spent on grooming between the treatment groups . The cuttlefish treated with 2% acetic acid plus 3% lidocaine also had a profoundly lower grooming time compared with the 2% acetic acid group (p = 0.012), demonstrating that 3% lidocaine reduced the cuttlefish’s grooming behaviour caused by 2% acetic acid injection.The cuttlefish administered with 0.5% acetic acid and 2% lidocaine simultaneously spent less time grooming compared with the 0.5% acetic acid group  showed that acetic acid did have a concentration-dependent effect on complex swimming trajectories where 10% had a profound impact on reducing complexities, followed by 5%, and then 1% had the least effect on these fish [Injection into the arm of the ctopuses ,27. The ese fish . The admese fish  and fishese fish ,29,30,31S. pharoaensis. This is one of the behavioural criteria that animals must fulfil to be considered of experiencing pain [The acetic acid test is a standard pain test and a model for exploring behavioural responses to acetic acid to determine the intensity of pain and also the effect of analgesics or other tested substances ,33. Thising pain  and provHirudo, that repeated activations of touch afferents (T cells) decrease both synaptic transmissions by nociceptive afferents (N cells) and the magnitude of a withdrawal reflex when N cells are stimulated [Grooming behaviour caused by the acetic acid may be similar to the grooming behaviour observed in octopus  and alsoimulated ,42. Whetimulated ,38,39. Iimulated ), althouIn conclusion, these results indicate that the application of a noxious, potentially painful stimulus induces grooming behaviour in cuttlefish; thus, exposure to low pH should be avoided to safeguard welfare. The grooming behaviour of the injection site may be an attempt to reduce the pain via the inhibition of the pain signal by stimulation touch receptors, but this remains to be investigated. Wound-directed behaviour does demonstrate that the animal is aware of the damage; thus, when subjecting these animals to any painful treatments in the laboratory, we should consider alleviating pain by the administration of pain-relieving drugs. Here, we injected 3% lidocaine at the site and prevented grooming behaviours elicited by acetic acid; thus, we can recommend this drug for use as a local inaesthetic. Future studies should investigate lidocaine’s efficacy in cuttlefish when subject to other potentially painful treatments.


Almost half a billion people world-wide suffer from disabling hearing loss. While hearing aids can partially compensate for this, a large proportion of users struggle to understand speech in situations with background noise. Here, we present a deep learning-based algorithm that selectively suppresses noise while maintaining speech signals. The algorithm restores speech intelligibility for hearing aid users to the level of control subjects with normal hearing. It consists of a deep network that is trained on a large custom database of noisy speech signals and is further optimized by a neural architecture search, using a novel deep learning-based metric for speech intelligibility. The network achieves state-of-the-art denoising on a range of human-graded assessments, generalizes across different noise categories and—in contrast to classic beamforming approaches—operates on a single microphone. The system runs in real time on a laptop, suggesting that large-scale deployment on hearing aid chips could be achieved within a few years. Deep learning-based denoising therefore holds the potential to improve the quality of life of millions of hearing impaired people soon. Nevertheless, over 80% of people who would benefit from use of hearing aids do not wear them6, with the majority of hearing aid owners who do not wear them citing difficulties with hearing in noisy situations as a main problem5.Hearing loss is a debilitating condition that is associated with a large range of negative health outcomes9. Non-spatial (single microphone) noise reduction algorithms employed in hearing aids have so far not been able to provide improvements in speech intelligibility15. A few recent studies have shown that deep learning-based denoising18 or separation of multiple competing speakers20 can provide improvements in speech intelligibility for cochlear implant users21 and hearing aid users with severe-profound22 hearing loss under fixed signal-to-noise (SNR) conditions18. For the majority of hearing aid users, with less severe hearing loss22, it is more challenging to provide intelligibility improvements through denoising. A very recent study has shown the ability of a deep learning based denoising system to moderately improve speech intelligibility for hearing aid users23. Our work builds upon these exciting results and demonstrates that deep learning based denoising may be used to provide large improvements in speech intelligibility for hearing aid users in the near future.Noise reduction in most commercially available hearing aids is done by introducing spatial selectivity, e.g., by beamforming, which improves speech intelligibility for frontal sources in the presence of predominantly non-frontal noise24 and AlphaFold25, we demonstrate that combining and scaling multiple cutting-edge methods leads to a drastic improvement in capabilities for denoising systems. In order to be adopted into real-world use in hearing aids, the denoising system needs to work for: 1) a wide variety of a-priori unknown speakers, noise types, and SNR values; 2) real-time processing; 3) users with mild to severe hearing loss. In this study we present a new deep learning-based denoising system that simultaneously addresses all of those points. Based on 150,000 human ratings of three datasets covering a wide range of speakers, noises, and SNRs, our model it is trained with thousands of hours of high-quality speech material and improves upon state-of-the-art denoising systems. It is also efficient enough, to be while being able to run on a laptop in real-time, i.e. requiring that the processing of inputs by the model is faster than the duration of the input. Most importantly, in live intelligibility tests with dynamically adapting SNRs, our system improves speech intelligibility for hearing aid users with moderate-severe hearing loss to levels comparable to those for normal hearing listeners without our denoising system.While some recent academic efforts are interested in similar questions, our work is an industry-academia collaboration with the target being a functional hearing aid, coming with the associated scope and complexity. Similar to recent deep learning models that showed strong improvements mostly due to scale, such as ChatGPT26 architecture, and predicts a complex-valued ideal ratio mask from the short-time Fourier transform of noisy speech signals  from human users. As obtaining MOS is time-consuming and expensive, they are typically only used to compare the performance of algorithms once they have been optimized, but not for the optimization procedure itselfversion “”. The pr35 using three test datasets, one of which  is commonly used as a performance baseline. We created two other test datasets (WHAMVox easy and WHAMVox hard) from the publicly available VOXCeleb237 speech and WHAM!38 noise datasets ets see “” to provine see “”. Note tWe collected MOS ratings from human listeners for the same sound samples with noisy speech (as a baseline), enhanced by our denoising algorithm, and enhanced by the comparison models Fig. A. Our deHuman listeners rated the samples processed with our denoising model as better than other models for a wide range of signal-to-noise ratios  test39 . The SRTs of hearing impaired subjects are higher with a median of − 3.3 dB . Activating our denoising system provides median changes of − 3.5 dB, − 3.5 dB, and − 2.8 dB for hearing impaired subjects , respectively for the OLSA, restaurant and traffic noise  is repeated in each block and combined with a residual connection after each layer repetition. If necessary, an additional projection (dense) layer is used to adapt the feature dimensions of the skip connection to match the shape of the tensor it is being added to.The encoder compresses the input using strided convolutions and the decoder reconstructs the compressed data back to its original dimensions using transposed convolutions. The encoder consists of 3 residual convolutional blocks, each containing several convolutional layers after which a strided convolution downsamples the data to decrease its time dimension. The blocks differ slightly in each stage and were selected by an evolutionary architecture searchThe decoder has its own 3 uniquely searched blocks, but with the same search space as the encoder. However, it replaces the down sampling strided convolutions after each block by a transposed convolution to up-sample the processed data back to its original dimensions. Additionally, the first residual connection of each block consists of a skip connection from the equivalent layer in the encoder.49.The bottleneck consists of two parts: a convolutional block, as above but without strided or transposed convolutions, followed by a hand-designed pyramid pooling block50. Spatially separable convolutions consist of subsequent distinct convolutional layers with variable kernel size in one spatial dimension (i.e. time or frequency), and a constant kernel size of 1 in the other dimensions. We distinguish two settings: (1) time first and (2) frequency first, to distinguish whether to apply a convolution in the time or frequency dimension first.The types of layers are limited to standard convolutional layers, depth-wise convolutional layers, spatial convolutions, and frequency/time first convolutionsThe exact architecture of the network is determined using an adapted evolutionary search. This search determines the types of layers, number of layers, dilations, skip connection locations, kernel sizes, and number of filters for each layer. The adapted evolutionary search performs a selection and mutation process. Initially, it creates a population of 100 random architectures and rates them with our predicted MOS score after 2000 training steps . It then removes architectures below the average MOS score and refills the population with mutated runs based off the best performing architectures. This is useful to weed out clearly underperforming candidates early on and reduce the computational demand of the search since it is not computationally feasible to train every network until convergence. We continuously repeat this process, creating hurdles after every 25,000 training steps to preselect promising candidates, advancing them, and restarting newly mutated runs from these candidates. Consequently, fewer architectures are trained for long periods of time, while the majority can be stopped early. The hurdles are adjusted based off the population at each training checkpoint including previous and new architectures.Mutations randomly modify parameters of the architecture. Any parameter, i.e., number of filters, layer type, etc., can mutate with a probability of 35%. However, we do not randomly set new values, but apply a limited change based off the parameter’s current value. This method finds adjacent architectures to the current best candidates. The evolutionary search is run until performance improvements stagnate.Throughout the network, each layer uses rectified linear unit (ReLU) activation functions except the last layer which uses a linear activation function. In total the network includes around 4 million parameters. We trained the network with a batch size of 16 samples and a length of 10 s (cut to 1.8 s to match the network input size) per sample, to predict the complex-valued ideal ratio mask of each sample using the mean squared error loss and optimize the weights with the Adam optimizer with a learning rate of 0.0001.The network input consists of mixed speech and noise inputs taken from a large database of speech and noise files. It consists of over 5000 h of speech and 2000 h of noise. The speech dataset includes a weighted combination of the following datasets: AVSpeech, Common Voice, LibriSpeech, VoxCeleb2, and a selection of podcasts downloaded from the internet. The noise dataset includes a weighted combination of the following collection of sound effect and noises: AudioSet, BBC Complete Sound Effect Library, and Soundsnap. The weighting/amount of each of the datasets was determined using a random search. Each mixed input waveform, sampled at 22.5 kHz, is converted to the frequency domain using the short-time Fourier transform (STFT) which uses a frame length 512, frame step 128 and the Hann window function. The network predicts the denoised STFT which is then converted back to a waveform. During testing the waveform was sent to the soundcard of the testing device, which in this study was a laptop. The algorithm runs in real-time on Ubuntu 16.04 on an Asus FX504GD-DM116 laptop with the following specifications: an Intel Core i5-8300H, 8 GB DDR4 RAM, and a NVIDIA GTX 1050 graphics card. To avoid problems with inconsistencies in the audio stack of the laptop and to reduce the computational demand, we chose a rather large output size of 4096 frames, together with 4096 frames lookahead, leading to a maximum total processing time of 370 ms . Note that the models we compare to ours generally do not run in real-time on the specified laptop, i.e. their processing time is longer than the given output duration. We did not attempt run-time optimizations of any of the models and instead focused on improving our network itself during development as the main goal of this study was to prove that deep learning generalizes well enough to be of high importance for future use in hearing applications. It is to be expected that, given engineering effort in the implementation, similar network models should be able to run on significantly smaller systems.51.Our custom speech quality metric is generated by a multi-stage neural network, which was trained to predict human listeners' opinion scores from noisy speech files rated by human listeners on Amazon Mechanical Turk (MTurk). The methods used to create this metric are described in detail by Diehl et alThe MOS ratings were obtained using Amazon Mechanical Turk. To ensure that ratings were of high quality, only workers with a Mechanical Turk Master’s qualification were accepted to work on the task. Workers rated sound files on a scale of 1.0 (bad) to 5.0 .Altogether the final dataset consisted of 15,962 files, with 94,225 ratings, giving an average of 5.9 ratings per file. When calculating the average rating for each sample and category, the trimmed mean of all ratings is taken, i.e. the lowest and highest rating(s) were ignored.52), STOI53, ViSQOL54, and PESQ55. We then used the trained MLP to predict the MOS from 600,000 unrated processed or unprocessed mixed speech and noise files from our datasets. We used this larger synthetic dataset of MLP-rated files to train our MOS prediction network described in the following section.To increase the size of the collected human-rated dataset, we trained a multilayer perceptron (MLP) to predict the MOS of each labelled sound file from a range of objective speech quality metrics, such as: SNR, mean squared error (MSE), mean log error, WSS, CEP  mixed speech and noise file as inputs. The STFT and MEL spectrogram from the inputs is passed to the network, which is used to predict the MOS of the noisy sample. The network was trained on the synthetic dataset of 600,000 clean and noisy files described in the previous section.Once trained, the MOS network evaluates the performance of the denoising network. The MOS network predicts one score for the unprocessed mixed speech and noise file and one for the same file after processing by the denoising network. The difference between the two scores in predicted MOS (delta-MOS) is taken as an evaluation metric. The evolutionary neural architecture search makes use of the delta-MOS as a target to find good hyperparameters and network structures for the denoising network.We evaluated the performance of our denoising network and of several state-of-the-art models, which were either downloaded from the author’s websites if pretrained models were available or reimplemented by ourselves following requests to the authors for available code.36 test set, commonly used to evaluate speech denoising models and 2 test sets consisting of publicly available VoxCeleb237 speech and WHAM! Noise38 files, separated into WHAMVox easy, covering SNR ranges − 12 to 27 dB, and WHAMVox hard, covering SNR ranges − 20 to 20 dB. None of the files in the 3 test sets were included in the data used to train the models. The datasets can be downloaded from: https://audatic-team.github.io/WHAMVox/. Sound files are available at: https://jelly-crush-c64.notion.site/Restoring-speech-intelligibility-for-hearing-aid-users-with-deep-learning-495b365b86bb406694b6efc926c78178.We performed evaluations on 3 test sets: the Valentini36 dataset is available at https://datashare.ed.ac.uk/handle/10283/2791. The test set consists of 824 files containing speech samples from two speakers  taken from the VCTK56 database and noises taken from the DEMAND57 database. Each speech file is mixed with a noise sample at an SNR in the range of − 1 to 17 dB.The Valentini38 Noise set contains 3000 files (samples with pre-mixed speech and noise) from which we removed all samples above an estimated − 12 dB SNR to reduce the probability of having audible speech in the noise files. Thus, the set was reduced to 1941 files with an average duration of ~ 10 s.The WHAM!37 speech dataset contains ~ 36,000 samples in its test set. To improve the quality of the files, we removed all samples with an estimated SNR below 20 dB and all files that are shorter than 8 s. This procedure reduced the number of audio files to ~ 5700 and left 116 distinct speakers in the test set, comprising 33% female and 67% male speakers. All female speaker files and a randomly selected equal amount of male speaker files were selected to balance genders.The VoxCeleb258 . We then randomly sampled a SNR value, a noise file and a speaker file and mixed them together to give a total of 1941 mixed files with 69 distinct speakers . We cropped files to their first 4 s to preserve the start of conversations and avoid audio files starting mid-sentence or word. For the WHAMVox hard test set we adjusted the SNR distribution, drawing from a normal distribution with mean 0 dB SNR and standard deviation 7. Before mixing, all files were normalized to have an RMS of − 20 decibels relative to full scale (dBFS), controlling the loudness.We controlled the SNR distribution of the mixed speech and noise files by sampling SNRs from a normal distribution with mean 8 dB SNR and standard deviation 7 that approximates the distribution of SNRs encountered in real world speech listening situations for older adults with mild to moderate hearing losshttps://audatic-team.github.io/WHAMVox/.Code and setup requirements to create the WHAMVox test set are available online: 59 for all models except for the DEMUCS34 model, where we used sox60 to be consistent with the methods listed on the authors’ website61.All sound files were downsampled from their original sampling rate to 22.05 kHz or 16 kHz as expected by the denoising model. Downsampling was performed using scipy.signal.resample_poly34 and MHANet33 models were obtained from the authors’ websites62. The third model we compared our model to, is the Sound of Silence35 model. As no code was available at the time of writing and no pretrained model was available from the author’s website, we reimplemented this model following the description from the paper35.We compared the results of our models to three state-of-the-art speech enhancement models. Pretrained DEMUCS63 and noise inputs drawn from the Audioset Noise  dataset64. All other model and training details are as specified in the original paper.Our implementation of the Sound of Silence model follows that described in the paper except for computation of the target silent interval mask, since in our experiments the original method performed poorly, mislabelling a high proportion of segments. Instead, we first took the STFT of the clean speech waveform, normalized the STFT magnitude to lie between − 1 and 1 and applied the same threshold (0.08) to the STFT magnitude to produce the target mask. We trained the model end-to-end using an even weighting of all three target losses described in the original paper with the ADAM optimizer, learning rate set to 0.001, batch size 8, for 100,000 training steps. We trained the model using speech inputs drawn from the AVSPEECH datasetThe experimental protocols employed were approved by the Ethics Committee of the Charité Medical School Berlin, Germany and concur with the Helsinki Declaration. All subjects gave their informed consent.Hearing impaired subjects were 16 German-speaking individuals  aged 38–72  with a binaural hearing loss of at least 30 dB and varying degrees of experience with hearing aid use (0.8–20 years). A single subject had a middle-ear disorder in the left ear, while all other subjects had sensorineural hearing loss. The following exclusion criteria were applied: hearing aids or cochlear implants insufficiently fitted to understand speech in quiet; the usage of central nervous system drugs  within 48 h before the study participation.We tested 17 normal hearing German-speaking individuals  aged 31–66  without any hearing problem in the past. Usage of central nervous system drugs  within 48 h before the study participation was an exclusion criterion.To determine the degree of hearing impairment, pure tone audiometry testing (0.25–8 kHz) was performed prior to the study. Hearing impaired subjects were tested under two conditions: once without hearing aid through air and bone conduction, and once with hearing aid, in the free field with the contralateral ear masked. In all conditions the pure-tone-average (PTA) was each determined using four test tones: 0.5, 1, 2 and 4 kHz.Averaged over all patients, the air conduction hearing thresholds .The normal hearing study subjects all fulfill the WHO criteria for normal hearing39 , a German speech comprehension test in noise). The measured value is the speech reception threshold (SRT), which is the signal-to-noise ratio (SNR) at which 50% of the words in a sentence are understood correctly.We evaluated the effectiveness of our deep learning-based denoising algorithm using the Oldenburger Satztest39, with five words per sentence. These sentences are grammatically correct, without semantic cohesion. Each sentence was mixed with one of three types of noise: speech-shaped noise , restaurant noise or traffic noise (both from our own datasets).Mixed speech and noise were played through the loudspeaker at varying SNRs while the subject’s SRT was measured. Speech consisted of OLSA sentencesThe noise level was fixed at 65 dB (SPL), while the speech level was adapted to determine the subject’s SRT according to the OLSA procedure. At the beginning the speech level was also at 65 dB (SPL) and was then adjusted according to the number of words correctly repeated. If three or more words were repeated correctly, the speech level was decreased . If fewer than three words were repeated correctly, the level was increased. One test consisted of 20 sentences. The corresponding increases and decreases in speech level are such that the target word error rate is 50%.65; (2) OLSA noise filtered by denoising system; (3) restaurant noise; (4) restaurant noise filtered by denoising system; (5) traffic noise; (6) traffic noise filtered by denoising system. The noises were presented in random order, but always starting with unfiltered noise followed directly by the sequence with the denoising system applied. The first 10 sentences of each block were ignored to allow for adaptation to the new test condition. The resulting SRT for each block was computed by taking the mean dB (SPL) of the final 10 sentences for that block. The signal to noise ratio (SNR) was calculated by subtracting the speech level from the noise level (kept constant at 65 dB (SPL)).In our study we performed with each subject 6 blocks of 20 sentences with different noise conditions: (1) OLSA noiseThe OLSA-Test requires each participant to be familiar with the procedure of the test. We therefore conducted a trial run with each subject before the measurements of the study.During the measurements, each hearing impaired participant wore their own hearing aid, adjusted to their individual hearing profile.Subject testing took place in a soundproof room. The testing setup is shown in Extended Data Fig. The distributions of the test results (SRT) are presented throughout as box-and-whiskers plots . For a comparison with literature data presented as mean and standard deviation the median absolute deviation (MAD) was calculated as a measure of variability .Statistical testing of SRT alterations between the two test conditions without or with the denoising system was performed with the Wilcoxon signed-rank test for matched pairs. To detect differences between several (more than 2) test conditions carried out with the same test group the Friedman test was used.The comparison of test results between different test subjects was performed using the Mann–Whitney-U-test. In all tests a result of p < 0.05 was considered significant.Supplementary Information.


Cochlear ischemia is hypothesized as one of the major etiologies of idiopathic sudden sensorineural hearing loss. Therefore, anticoagulant therapies are designed to be beneficial in certain patients with this condition.This study aimed to determine which patients with idiopathic sudden sensorineural hearing loss would benefit from heparin treatment as adjuvant therapy.In total, 134 patients who underwent magnetic resonance imaging for unilateral idiopathic sudden sensorineural hearing loss at a tertiary referral hospital between January 2014 and December 2018 were included in this retrospective study. All patients received Intratympanic steroid injections or heparin therapy plus oral corticosteroids. Radiological parameters of the vertebrobasilar system and clinical data from pre- and post-treatment assessments were analyzed.p = 0.036), while the 69 patients with mild-to-moderate idiopathic sudden sensorineural hearing loss did not (p = 0.950). Additionally, the degree of basilar artery tortuosity was significantly associated with the degree of hearing impairment in the severe-to-profound idiopathic sudden sensorineural hearing loss group (p = 0.015). When idiopathic sudden sensorineural hearing loss occurred on the opposite side to basilar artery displacement, the improvement of hearing was significantly greater in patients treated with heparin than in those treated with intratympanic steroids (p =  0.041).Most patients (71.6%) had a tortuous basilar artery The 65 patients with severe-to-profound idiopathic sudden sensorineural hearing loss showed a significant relationship between idiopathic sudden sensorineural hearing loss laterality and basilar artery displacement to the opposite side (In a subset of patients with severe-to-profound idiopathic sudden sensorineural hearing loss, basilar artery tortuosity had a significant directional relationship with idiopathic sudden sensorineural hearing loss laterality. In these selected patients, a significant effect of heparin therapy on improving hearing was observed. Cochlear ischemia caused by atherothrombotic events is hypothesized to be one of the major etiologies of Idiopathic Sudden Sensorineural Hearing Loss (ISSNHL).Blood to the cochlea is supplied by the internal auditory artery, which usually arises from a branch of the Basilar Artery (BA). Because the BA is formed by the union of two Vertebral Arteries (VA) that are commonly asymmetric in size, tortuosity of the BA is frequently observed. Morphologic and hemodynamic changes in the tortuous BA can contribute to the development of atherothrombosis on the side contralateral to its angulation.Oral corticosteroids are currently widely used as the standard treatment for ISSNHL. Although there are many observational studies that suggest a treatment benefit of corticosteroid treatment, additional therapies are often required due to the lack of effectiveness of steroids based on randomized controlled trials.The study protocol and a waiver of consent for retrospective chart review were approved by the Institutional Review Board of the Clinical Research Institute (GBIRB2019-419). The study was carried out in accordance with the Declaration of Helsinki.This was a retrospective cohort study performed in a tertiary referral center. Electronic medical records were reviewed for the period between January 2014 and December 2018, and adult patients (> 18 years old) who were diagnosed with unilateral ISSNHL and underwent temporal bone MRI were considered for inclusion. Patients who had any identifiable cause of hearing loss were excluded. A total of 134 patients were finally included in this study.All of the patients were admitted and started on treatment with a standard oral steroid protocol (a course of 48 mg methylprednisolone tapered over 11 days) less than 7 days after the onset of hearing loss. In addition to systemic steroid therapy, patients received either heparin  or intratympanic steroid injection  as adjuvant therapy. Patients who had hypertension, diabetes, or cardiovascular disease were also given specific treatment for these conditions along with the oral steroid and adjuvant therapy.Hearing was evaluated using pure tone audiometry at the initial visit and at the three-month followup. The Pure Tone Average (PTA) was calculated as the arithmetic mean of the hearing thresholds (dB) at 0.5, 1, 2, and 4 kHz in the affected ear.Temporal bone MRI was performed using a 3.0 T scanner . Morphologic characteristics of the vertebrobasilar system were analyzed blinded to the clinical information. Images were analyzed to determine the tortuosity (side and degree) and the diameter of the BA, and the presence of a dominant VA. The transverse diameter of the BA at the midpontine level was measured on axial T2-weighted images.t-tests were used. For skewed variables, groups were compared using the Mann-Whitney U test. The relationship between the side affected by hearing loss and the radiological characteristics of the vertebrobasilar system was assessed using the linear-by-linear association test; p-values of < 0.05 were considered statistically significant.All statistical analyses were performed using SPSS software . Descriptive data are reported as counts  or mean ± Standard Deviation (SD), as appropriate. The chi square test and Fisher’s exact test were used to compare categorical variables, as appropriate for the data. For continuous variables with a normal distribution, Student's p =  0.010 and < 0.001, respectively). The rates of vertigo at presentation and the follow-up PTA were higher in patients with severe-to-profound hearing loss.We included a total of 134 patients (aged 52.2 ± 11.9 years) divided in two groups: those with mild-to-moderate hearing loss (n = 69) and those with severe-to-profound hearing loss (n = 65). The mean initial PTA in the affected ears was 52.2 ± 12.8 dB for the mild-to-moderate group and 92.9 ± 16.3 dB for the severe-to-profound group. The overall radiological assessment demonstrated that 71.6% (96/134) of the patients had a tortuous BA and 67.1% (90/134) had an asymmetric VA . The meap =  0.152, linear-by-linear association). We further analyzed the directional relationship within each hearing level group . p  = 0.950). On the other hand, in the severe-to-profound hearing loss group, 48 (73.8%) patients had lateral displacement of the BA (≥ Grade 1), and a significant directional relationship was detected, with hearing loss more likely to be on the opposite side to BA displacement (p =  0.036). Additionally, the degree of hearing impairment in the severe-to-profound hearing loss subgroup of patients with a tortuous BA was associated with the degree of BA tortuosity (p =  0.015).In this study, right-sided hearing loss (identified in 57.5% of patients) and right-sided BA displacement (identified in 41.0%) were more frequently seen than left-sided hearing loss and displacement. However, there was no significant directional relationship between the sides of hearing loss and BA displacement (rtuosity . Our subp  = 0.108). With regard to the initial PTA, the ITS group had poorer hearing than the heparin group (p  = 0.015) (p =  0.108) showed worsening of hearing from initial hearing level, which was between 1.25–12.5 dB worse. To select cases that were more likely to experience a hearing improvement following heparin therapy, we hypothesized that anticoagulant therapy may be more efficient in the subgroup of patients who had ISSNHL of vascular origin. Among the 65 patients in the severe-to-profound hearing loss group, 35 patients had hearing loss on the contralateral side of BA displacement. Our analysis of this subgroup showed that these patients achieved greater benefit from heparin than ITS as an adjuvant therapy (p =  0.041).The above results indicate that our hypothesis on vascular etiology was valid only in the severe-to-profound hearing loss group. Thus, further analyses of the efficacy of adjuvant therapies were performed in patients with initial PTA ≥ 70 dB, all of whom received adjuvant therapy. The frequency of vertigo was 36.2% in patients treated with ITS  vs. 16.7% in patients treated with heparin  (= 0.015) . However= 0.015) . Among 1 therapy . In the There were no significant complications during or after heparin therapy, including hemorrhage, hypersensitivity, thrombocytopenia, or priapism. In addition, no patient experienced serious adverse events related to ITS, including tympanic membrane perforation, otitis media, and vertigo.Interruption of the vascular supply and resultant cochlear ischemia is thought to contribute to ISSNHL in some cases. In the context of this vascular etiology, heparin adjuvant therapy to improve cochlear blood flow has been implemented for the treatment of some ISSNHL cases in our department. Since treatment decisions were generally based on the clinician’s preference rather than on findings that implied an underlying etiology, this intervention improved hearing in some patients but not others. Therefore, this study was designed to identify possible vascular causes for ISSNHL using MRI of the vertebrobasilar system and to help determine which patients will benefit from heparin adjuvant therapy. It is of particular clinical importance to note that both a severe-to-profound degree of initial hearing impairment (PTA ≥ 70 dB) and the presence of hearing loss on the opposite side to that of BA displacement were associated with an increased chance of success of heparin therapy.The present study is the first to use MRI to evaluate the benefit profile of anticoagulant adjuvant therapy in patients with unilateral ISSNHL. The current analyses provide evidence that anticoagulant therapy was associated with a better hearing outcome in the subset of patients for whom a vascular etiology was inferred from MRI findings regarding the vertebrobasilar system. A strength of this study is that routine evaluation for retrocochlear pathology was performed using temporal bone MRI for cases of sudden sensorineural hearing loss. Considering the significant prevalence (4.4%−13.75%) of pathogenic MRI abnormalities, including vestibular schwannoma and pontine infarction, in patients with sudden sensorineural hearing loss,Some previous studies have reviewed the relationship between ISSNHL and the vertebrobasilar system. In 2016, Kim et al. conducted a study of 121 patients to analyze the characteristics of the vertebrobasilar system in relation to ISSNHL laterality.Currently, it is impossible to directly detect cochlear ischemia using a noninvasive method. Thus, it is difficult to precisely determine a vascular etiology of ISSNHL without pathological confirmation. On the other hand, the acute onset of sensorineural hearing loss in patients with vertebrobasilar ischemic stroke is commonly expected to result from a vascular cause, and this diagnosis is easily made using MRI.Interestingly, the initial degree of hearing impairment had a significant influence on the directional relationship between hearing loss laterality and the direction of BA displacement. The group of patients who had mild-to-moderate hearing loss (PTA < 70 dB) at initial presentation did not show a relationship between the laterality of hearing loss and the side of BA displacement A. CommonThe contribution of BA tortuosity to cochlear ischemia can be explained by the effect of traction of BA branches, as well as a procoagulant state associated with slow blood flow and reduced shear stress on the concave side of the vessel.This study has some limitations. The main limitation are lack of randomization and sample size because of its retrospective nature. The analysis of the effectiveness of adjuvant therapy for treating patients with ISSNHL was inferior to that of high quality randomized clinical trials. However, it is believed that significant bias may be reduced by the selection of adjuvant therapy without knowing the disease status. Patients were allocated randomly to one of four physicians in our clinic, and every physician used only one protocol consistently during study period. Second, this study only relied on clinical characteristics, audiological measures, and MRI findings of the vertebrobasilar system to diagnose cochlear ischemia. Therefore, the suggested explanations for the contribution of BA tortuosity to ISSNHL remains speculative. To overcome these limitations, randomized controlled prospective study of clinical cases is needed to confirm the results of this study.In a subset of patients with severe-to-profound ISSNHL, BA tortuosity had a significant directional relationship with ISSNHL laterality. In these selected patients who meet specific conditions, a significantly positive therapeutic effect of heparin on improving the recovery of hearing was observed.Gachon University Gil Medical Center (Grant number: FRD2019-01).This work was supported by the The author declares no conflicts of interest.


In newborn hearing screening little importance is attributed to changes in the middle ear. Children with secretory otitis in the neonatal period are at risk for developing otitis media in the first year of life.Aim: To determine if children who failed the hearing screening because of conductive hearing loss have more episodes of conductive hearing impairment during their first years of life.Materials and Methods: The study group comprised 62 children who failed the screening for conductive impairment. The control was made up of 221 who passed. Both had audiologic and otolaryngological assistance and were compared regarding the occurrence of conductive disorder. Were used the Fisher's Exact test for statistical analysis and logistic regression models. The study was prospective and retrospective.Results: Children who failed the screening by conductive disorder had more episodes of otitis media during the first year of life than those who did not fail, with statistically significant difference.Conclusion: Infants who failed the screening in the first month of life for conductive alteration are more likely to experience otitis in the first year of life. The high incidence of otitis indicates the need for joint action with otolaryngologist for diagnosis of such changes. Anatomical and physiological integrity of the central and peripheral auditory system is a prerequisite for normal language acquisition and development .Therefore, the impact of undetected hearing loss on the development of language and socialization of children has given rise to neonatal screening programs.Northern and Downs (1991)Intermittent alterations due to conductive hearing loss because of recurring otitis may affect the ability to process sound stimuli; in such cases, acoustic parameters vary according to temporary or period hearing loss .Secretory otitis media or otitis media with effusion is the most frequent cause of conductive hearing loss in children in developed countries. It may be defined as the presence of fluid in the middle ear with no signs or symptoms of acute infection that occurs in the first years of life. It may be accompanied by mild to moderate episodic, variable, conductive hearing loss never over 50 dB .Secretory otitis media is rare in the first 6 months of life. Its incidence increases markedly from 6 to 12 months of age, reaching about 13 to 15% at age 12 months. The peak frequency occurs from age 2 to 4 years; at this age, 20% of all children experience secretory otitis media .Little importance has been given to middle ear alterations – which are transitory – in neonatal hearing screening programs. Doyle et al. (2004)Sensory deprivation due to secretory otitis media may affect speech perception and understanding, especially in noisy ambiences; Language development may also be affected. This is further compounded by the number and duration of episodes of this disease.Fluctuating hearing loss due to middle ear diseases in the first years of life may result in altered auditory processing, which affects learning.Thus, prevention, detection, and especially monitoring for at least a year is essential for the newborn that failed in conductive hearing screening tests. Middle ear alterations (otitis), which peak from ages 6 to 12 years, may persist; this age range is important because this is when the auditory system and language acquisition take place.Therefore, the purpose of this study was to verify whether neonates that failed the conductive test hearing screening are more likely to present middle ear alterations during the first year of life, compared to those that passed hearing screening.The institutional review board analyzed and approved this study on 21 December 2007 (protocol no. 1561/07).Parents and/or caretakers that agreed to have their children participate in this study were duly informed and signed a free informed consent form, as required by the ethics of research in human beings.Children that presented every six months for hearing monitoring were included; these children underwent at least three assessments of hearing . Children with neurological conditions, malformations, or sensorineural hearing loss were excluded from this study. The study population was allocated to two groups: a control group consisting of children that passed neonatal hearing screening, and a study group consisting of children that failed neonatal hearing screening, which was confirmed by tympanometry and an otorhinolaryn-gological evaluation.This was a retrospective and prospective study. For the retrospective study, the medical files of 217 preterm children born from 2003 to 2006 were assessed; these children were seen in the multidisciplinary monitoring program for high risk neonates. The prospective study consisted of following-up 66 children born in 2007, of which 31 were term births and 35 were born preterm.Both groups were compared to test the hypothesis that children in the study group had a higher rate of conductive hearing loss because of secretory otitis media within the fits year of life, compared to controls. The frequency of conductive hearing loss in children that failed in the hearing screening due to conductive loss was analyzed during the 12-month monitoring period.The following tests were applied for testing hearing: transient otoacoustic evoked emissions (TOAE), immittance testing at 226Hz, behavioral observation, investigation of the cochleo-palpebral reflex, visual reinforcement audiometry, and an otorhinolaryngological evaluation.An ILO 292 – Otoacoustic Emissions Analyzer  coupled to a conventional computer was used for TOAE testing. TOAE were considered as present when the signal-to-noise ratio was equal to or higher than 3 dB at 1,500 Hz and equal to or higher than 6 dB at 2,000 Hz, 3,000 Hz and 4,000 Hz, and when general reproducibility was equal to or higher than 50% with sound stability equal to or higher than 70%, as proposed by Finitzo et al. (1998)7 and recommended by Azevedo (2003).An Interacoustics AZ7 manual impedance audiometer (226 Hz probe) was used for immittance testing. A type A tympanometric curve was considered as normal (Jerger 1970);9 type B and C curves were considered as altered (Jerger 1970).The behavioral assessment consisted of a survey of attention responses, source searching and location of music instrument sounds from 50 to 90 dBSPL, and investigation of the cochleo-palpebral reflex with agogô bells (100 dBNPS); Azevedo's (1995) age adaptation criterion was applied.An Interacoustics PA 5 pediatric audiometer was used for visual reinforcement audiometry in children aged from 6 to 12 months at 500 Hz, 1,000 Hz, 2,000 Hz and 4,000 Hz in free field. The stimulus was delivered 20 cm from the right and left ear lobes at decreasing intensities; a red light stimulus was delivered when the child moved the head towards the source of sound. The normal range in the free field evaluation was 40-60 dBHL in children aged from 6 to 9 months, and 20-40 dBHL in children aged from 9 to 13 months .The otorhinolaryngological evaluation consisted of otoscopy: an otorhinolaryngologist examined the newborn with an otoscopy to assess the status of the outer ear canal and the tympanic membrane. For our purposes, the tympanic membrane was classified as normal or altered . The physician that carried out these exams has over 15 year's professional experience with neonates. Failure due to conductive hearing loss in screening at birth was defined when TOAE and the cochleo-palpebral reflex were absent, when there was a type B tympanometric curve, when otoscopy was consistent with secretory otitis media, and when post-therapeutic/surgical exams were normal. Conductive hearing loss was defined as present when elevated pure tones for the age evoked minimal responses, TOAE and the cochleo-palpebral reflex were absent, and tympanic curves and otoscopy were altered.The logistic regression model and Fisher's exact test were applied to verify whether there were statistically significant differences on the occurrence of conductive hearing loss between the groups. Differences were considered as statistically significant differences when the p-value was below (5%). Significant values are marked with an asterisk (*).The prospective study consisted of monitoring 66 children who were born in 2007; 31 were female and 35 were male; 31 were term births and 35 were pre-term births.Analysis of the occurrence of conductive hearing loss in each group revealed that there was a statistically significant difference (p=0.0097*). The chance of a newborn in the control group to not present conductive hearing loss within the first year of life was 4.29 times higher than the chance of a newborn in the study group to not present conductive hearing loss .The retrospective study consisted of analyzing the medical files of 217 children of preterm births from 2003 to 2006; there were 115 male and 102 female subjects, all included in the multidisciplinary monitoring program for high risk neonates. The study group comprised children that failed the hearing screening assessment because of conductive hearing loss; the control group consisted of children that did not fail in hearing screening.Follow-up of newborn subjects across 12 months after hearing screening revealed that most of the children presented at least one episode of otitis.Although males had a higher occurrence of conductive hearing loss, this difference was not statistically significant  and 10.Among the middle ear changes in childhood episodes of recurring and/or persistent otitis and temporary hearing losses have come to the attention of healthcare professionals.The occurrence of conductive hearing loss due to secretory otitis media in children that failed in hearing screening (conductive hearing loss) while monitored during 12 months was analyzed.The results were similar in both studies; the discussion, therefore, will be done jointly.Analysis of the occurrence of conductive hearing loss in both groups revealed that there was a statistically significant difference between the study group and the control group; this result was common to the prospective and retrospective studies  and 6.We found in the prospective study that 16 children (57.1%) in the study group presented conductive hearing loss within the first year of life; in the control group this number was nine (23.7%). These results are similar to those of Doyle et al. (2004);6 these authors studied whether neonates with persistent middle ear effusion at 30 to 48 hours of life had or not an increased tendency to present otitis media within the first year of life compared to neonates with no effusion. They found that eight children (58%) of 14 in the study group presented otitis media in the first year of life; three (20%) of 15 children in the control group presented otitis media in the first year of life. This difference was statistically significant, as was the case in the present study.Although there was a higher rate of conductive hearing loss in the study group, children in the control group also presented conductive hearing loss within the first year of life: 23.7% in the prospective study, and 12.6% in the retrospective study  and 6.Conductive hearing loss may be a complication of otitis media, especially secretory otitis media. This condition is one of the most common diseases in childhood .Observations in the present study showed that neonates that had otitis in the neonatal period (1st month of life) had a higher possibility of presenting other episodes of otitis within 12 months. This finding is similar to Saes et al.'s (2005)Paparella (1972)Although males had a higher rate of conductive hearing loss, this difference was not statistically significant  and 10. Studies have been made to find in which of the assessments (2nd assessment at six months and a 3rd assessment at 12 months) the rate of conductive hearing loss was higher among the children with conductive hearing loss within 12 months of life. The peak occurrence of conductive hearing loss in the study group (in both studies) was age six months   and 7. TEngel et al. (1999)Saes et al. (2005)Monitoring of neonates in 12 months after hearing screening showed that there was only one episode or conductive hearing loss (due to otitis) per child after the second assessment in the prospective and retrospective studies.There was a higher occurrence of only one episode of conductive loss in both studies  and 8. TThese results show that identifying conductive hearing loss in neonatal and infant hearing screening is an important goal so that prompt and appropriate interventions may be undertaken; although it may be transitory, conductive hearing loss may result in altered language acquisition and auditory processing. Several studies in the literature we reviewed have underlined the importance of the diagnosis of conductive losses (Northern, Downs, 1991A higher occurrence of otitis in children that fail in neonatal hearing points at the need for joint work with otorhinolaryngologists. Thus, it is essential for such a professional to be part of the neonatal hearing screening team and to participate in audiological monitoring programs of children.Analysis of our results showed that neonates who failed in hearing screening done in the first months of life- because of secretory otitis media – have a higher chance of developing episodes of otitis, especially between 6 and 12 months of life. A second conclusion is that neonatal hearing screening programs require measures by otorhinolaryngologists to diagnose auditory changes, especially in the middle ear, which may result in future auditory processing losses, with resulting learning disabilities.


European Academy of Neurology (EAN) /Peripheral Nerve Society (PNS) Guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy,” has been published recently (The second revision of the “Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) diagnostic criteria,” now called “recently . These nrecently . This upChronic Inflammatory Polyradiculoneuropathy” (CIP)  of 26 patients was degeneration of myelinated fibers into linear rows of myelin ovoids and balls .In a seminal paper (1975), Dyck et al. isolated (from chronic idiopathic polyneuropathies) a subgroup of 53 patients who could be identified clinically as having a grossly symmetric, sensorimotor polyneuropathy, which they called “recurring and relapsing neuritis” . In 1982, Dyck et al. used, for the first time, the term “CIDP”  might be too restrictive; many neurologists and electrophysiologists noting the presence of significant axonal lesions may miss the diagnosis of CIP which, in most cases, respond to immunosuppressive/immunomodulatory treatments: positive randomized control trials have confirmed the efficiency of intravenous immunoglobulin (IVIg) and plasma exchanges in this disorder   should be very helpful (” (CIAP) ; neverthThe causes of axonal loss, which correlate with permanent clinical disability are poorly understood; nevertheless, several mechanisms are plausible. Axonal loss is usually considered as a secondary event in demyelinating disorders and its severity has implications for the diagnosis and prognosis; nevertheless recent studies indicate that axonal damage might also occur early in the disease . CIDP inIt is known that the lesions of auto-immune peripheral neuropathy (characterized by inflammatory cells and edema) are most severe at the nerve roots and the proximal parts of the nerves, and may also be diffuse throughout the length of peripheral nerves; Dyck et al. have suggested that these lesions might determine transection of nerve fibers and induce distal Wallerian degeneration . Such chSome patients diagnosed  as “CIDP” were found to have antibodies  against some components of the paranodal junctions: Neurofascin-155 (NF155), Contactin-1 (CNTN1), and Contactin-associated protein-1 (Caspr1). These patients usually present a peripheral neuropathy with sub-acute onset, chronic severe clinical course  and unresponsiveness to IVIg therapy . The lesAxonal involvement appears during the course of many chronic auto-immune peripheral neuropathy considered as “primarily demyelinating” (particularly during the course of CIDP), and also characterizes the acquired “paranodopathies.” Over time, axonal involvement becomes more severe and persistent, so that demyelinating lesions may be difficult to identify in some cases : such patients, sometimes wrongly considered as presenting “axonal peripheral neuropathy,” are not being treated correctly . Anyway, as we stressed it recently, it is important to acknowledge that the current EAN/PNS recently published criteria have made an important step in recognizing that clinical and laboratory evidence, and ultimately response to treatment must be taken into account besides electrodiagnostic criteria, to confirm the diagnosis of CIDP . It mustJ-MV contributed with the original conception of the paper. J-MV and SM drafted the manuscript. ND, PC, and LM provided a critical review of the text. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Hearing difficulty may adversely impact patient-provider communication and be exacerbated by the presence of other conditions like dementia. We examined the association between reported Alzheimer’s disease/dementia and reported difficulty communicating with providers. Using the 2019 Medicare Current Beneficiary Survey, we included participants were aged ≥65 years who reported functional difficulty hearing. Exposure was the presence of reported Alzheimer’s disease/dementia. Our outcome is reported difficulty communicating with medical providers. Multivariate logistic regression was used for association between the added presence of dementia and reported difficulty communicating with healthcare providers. Among 5,535 beneficiaries reporting hearing difficulty, diagnosis of Alzheimer’s disease or another dementia showed 2.76(95%CI:1.97-3.87) times greater odds of reporting difficulty communicating with providers compared to not reporting dementia. In summary, older adults with reported hearing difficulty and dementia may have increased difficulty communicating with medical providers. Findings suggest hearing management may aid in improving health outcomes for adults with dementia.


Hearing loss is conceptualized as any impairment of the ability to hear and/or detect speech or environment sounds, regardless of cause, type, or degree. It may occur at different stages of life; during pregnancy or childbirth, in childhood, adulthood or old age. It should be noted that aging is the most common cause of sensorineural hearing loss followed by noise-induced hearing loss, and both are closely related to the formation of reactive oxygen species. Dietary antioxidant supplementation has been employed as a therapeutic strategy to prevent and/or delay the risks of major human diseases.To assess randomized clinical trials to determine the effect of antioxidant supplementation on the auditory thresholds in patients of different age groups with sensorineural hearing loss.This systematic review consisted of a search in the following databases: MEDLINE, CENTRAL, ScienceDirect, Scopus, Web of Science, LILACS, SciELO and ClinicalTrials.gov. Additionally, the gray literature was also searched. The search strategy included terms related to the intervention (antioxidant supplementation), primary outcome , as well as terms related to randomized clinical trials to improve search sensitivity.p < 0.0001) when compared to the NAC group and the ginseng group, whereas at 6 kHz, the threshold increase was higher in the control group , but no statistically significant differences were found between groups.Based on 977 potentially relevant records identified through the search in the databases, ten full-text publications were retrieved for further evaluation. The increase in threshold at the 4 kHz frequency was statistically higher in the control group (1.89 [1.01–2.78], Ginseng was the antioxidant agent that showed the best effect in preventing auditory threshold worsening at the frequency of 4 kHz, but not at 6 kHz in patients with sensorineural hearing loss caused by exposure to high sound pressure levels. There was no improvement in the thresholds with vitamin E supplementation. The integrity of the auditory system is important for an individual's communication and social interaction.Hearing loss is described as any impairment of the ability to hear and/or detect speech or environment sounds, regardless of cause, type or degree, and may occur at different stages of life; during pregnancy or childbirth, in childhood, adulthood or old age.The main causes of congenital hearing loss are genetic, congenital infections and use of ototoxic drugs during pregnancy. Acquired hearing loss can result from several factors including agenetic predisposition, meningitis sequelae, exposure to noise, aging, and the use of ototoxic drugs; in some situations, the etiology remains unknown.Aging is the most prevalent cause of sensorineural hearing loss, followed by noise-induced hearing loss as the second most frequent cause, and both are closely linked to the formation of reactive oxygen species (ROS), which are responsible for several types of damage to biological molecules present in the cochlea, as well as for the development of several other human diseases. In view of this, it would be desirable to be able to inactivate or reduce the formation of these free radicals, for example, by the use of antioxidants, agents that can inhibit or reduce damage in cells caused by free radicals.Foods, especially fruits, vegetables and legumes, also contain antioxidants, such as Vitamins C, E and A, chlorophyllin, flavonoids, carotenoids, curcumin, and others that can restrict the dissemination of chain reactions and free radical-induced damage.Thus, the present meta-analysis aimed to evaluate randomized clinical trials to determine the effect of antioxidant supplementation on the auditory threshold in sensorineural hearing loss in patients of different age groups.http://www.crd.york.ac.uk/PROSPERO), (http://www.crd.york.ac.uk/PROSPERO), under n. CRD42015027677. Following the PRISMA criteria, the questions addressed in the objective refer to the PICO strategy, with patients being those of different ages with sensorineural hearing loss, while the intervention corresponds to the supplementation with antioxidants compared with subjects who did not receive supplementation. The results are related to auditory thresholds and the design of the assessed studies was the randomized clinical trial.This systematic review sought to answer the following question: Have patients of different ages with sensorineural hearing loss who received supplementation with antioxidants exhibited improved auditory thresholds? The present meta-analysis is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement.The following databases were searched until June 2016: MEDLINE, CENTRAL, ScienceDirect, Scopus, Web of Science, LILACS, SciELO and ClinicalTrials.gov. Additionally, the following gray literature databases were also searched: OpenGrey.eu, DissOnline.de, NYAM.org and ClinicalEvidence.com. There was no manual search of the included articles and experts in the area were not contacted to avoid the risk of bias.Only randomized clinical trials that met the following criteria were included: 1) individuals who were diagnosed with sensorineural hearing loss ; 2) presence of a group submitted to supplementation with antioxidants through oral route  and a control group. There were no restrictions regarding gender, ethnicity or comorbidities. At the least, the studies needed to have assessed the auditory threshold as a result and to report the mean values found or the differences between the mean values.The exclusion criteria were: 1) studies where dietary intervention was not related to hearing loss evaluation; 2) duplicate publications.The titles and abstracts of the retrieved articles were independently assessed by two investigators who were not blinded to the authors or titles of journals. The full versions of potentially eligible articles were retrieved for further assessment.The primary outcome investigated in the studies was the auditory threshold improvement after antioxidant supplementation, after previous identification of the type of hearing loss verified and the evaluation tool used. Additionally, factors associated with the use of antioxidants, such as the type of substance used, the amount of antioxidant intake and the time of supplementation, were assessed as a secondary outcome.All necessary information was extracted from the published articles, protocols and comments related to each study and where necessary, the authors were contacted for additional information. For studies that had more than two experimental groups, the most appropriate for the proposed objective was chosen by the authors. Any disagreements were resolved by consensus. In cases where there was no consensus, a third author was asked to make the final decision.In addition to the outcome data, we also extracted the authors’ names, study title, year of publication, country, age range of the groups, number of subjects in each group, type and degree of hearing loss per ear. A standard form for data storage was created based on the model adopted by Cochrane.The risk of bias was analyzed according to the recommendations of the Cochrane HandbookThe quality of the studies was evaluated by two independent researchers in five categories: generation of the appropriate sequence; allocation concealment; blinding of the participants, the researcher and the evaluators; handling of missing data for subsequent final judgment.The auditory threshold improvement after antioxidant supplementation was analyzed. The effects of the treatment through the assays were combined, and the weighted mean difference for the outcome measures was calculated.α value <0.05 was considered statistically significant. When it was not possible to obtain adequate data for analysis, the Cochrane recommendations were followed.For this, a random effects model was used as a measure of the effect of the mean difference between the groups and as a statistical method of analysis. An I2 test. A value of p < 0.10 was considered statistically significant. When necessary, study characteristics considered as potential sources of heterogeneity were included in a subgroup analysis. In addition, in case of heterogeneity, studies were removed, one by one, to investigate whether the study removed was the source of heterogeneity.Statistical heterogeneity between the studies was tested using the Cochran test and inconsistency was tested using the All analyses were performed using the RevMan 5.3 software (Cochran Collaboration).Based on 977 potentially relevant records identified through the search in the databases, ten full-text publications were retrieved for further evaluation. Of these, five were excluded after the full-text analysis, five articles were included in the qualitative analysis and of these, four in the quantitative analysis . The floAmong the five excluded studies, the work of Kaya et al.The study by Schmitz et al.The risk of bias in studies at the primary outcome level is shown in When considering the diversity of the objectives and methodologies of the selected articles, quantitative data analyses were performed by combining articles that showed results in common. Although Doosti et al.p = 0.24), there were no statistically significant differences among the groups.Although the control group showed a higher risk of auditory threshold worsening  when compared to the NAC group and the ginseng group.Threshold increase was statistically higher in the control group ; however, no statistically significant differences were found between groups.Threshold increase was higher in the control group . The four studies had, in addition to antioxidant supplementation, the use of concomitant drugs, with the intervention for supplementation being chosen, and one study had more than two intervention groups; the groups that better fit the analysis were determined by consensus.The studies2 + 5% CO2) for 30 min four times daily, whereas Group S received Vitamin E (400 mg twice daily) in addition to the Group C intervention. The recovery rate, calculated as the hearing gain divided by the hearing level difference between the affected individuals and affected ears, was greater than 75% in 41 of the 66 (62.12%) patients included in the study. This rate was reached in 26 (78.78%) patients in Group S (treated with Vitamin E), compared with 15 (45.45%) patients in the control group (Group C). There was improvement in patients treated with the addition of Vitamin E, but the authors recommended further studies to better understand the role of antioxidants in sudden deafness.The study by JoachimsAiming to assess the otoprotective effect of Vitamin E on the ototoxic effect of gentamicin, Kharkeli et al.n” of participants of each study group  as well as their respective percentages of improvement. Although both studied the effect of the same antioxidant on sensorineural hearing loss, the causes of this loss were different in each of the studies. Whereas in the study by Joachims,These two studies were the only ones that showed the “Considering that few articles were found using antioxidant supplementation aiming to evaluate auditory protection and improvement, and that the studies found were not grouped in the same category, with respect to the studied antioxidant or the cause of the sensorineural hearing loss, as well as small sample sizes, the studies were considered fragile and signaled a need to carry out other studies on this topic.n = 120) was divided into four groups that received the following treatments: dry extract of ginkgo biloba (120 mg/day), α-lipoic acid (60 mg/day) and vitamin C (600 mg/day), papaverine hydrochloride (100 mg/day) and Vitamin E (400 mg/day) or placebo. All participants were assessed at enrollment and after 6 months, using pure-tone audiometry thresholds (by means and isolated frequencies) and the percentage of the Speech Recognition Index (SRI). The results revealed no statistically significant changes in the auditory thresholds after the treatments during the study period.Polanski and CruzThe study by Doosti et al.n = 16) corresponding to those who did not receive antioxidant drugs; 2) NAC group (n = 16) that received oral N-acetyl-cysteine (1200 mg/day) and; 3) ginseng group (n = 16) who received the oral antioxidant (200 mg/day). Pure-tone and high-frequency audiometries were performed on the first day and 15 days after the intervention. The results showed a temporary improvement in the noise-induced thresholds for the NAC Group and the ginseng group at the 4, 6 and 16 kHz frequencies (p < 0.001) in both ears. Moreover, the otoprotective effects were higher in the NAC Group. Thus, the study shows that NAC and ginseng can reduce the impact of occupational noise to which workers are exposed and recommend further studies to prove the benefits of antioxidant use in hearing conservation programs.The authors randomly separated 48 workers exposed to continuous noise in a textile factory in three groups: 1) control group , one of the main antioxidant enzymes, which can neutralize the noise effectsThe fact that the antioxidant agent delayed hearing threshold worsening at the specific frequency of 4 kHz may have been determined because that specific group of cells was the most activated during exposure to loud noises. This activation occurs through the three main mechanism of action: 1) resonance of the external auditory canal that occurs, in average, at the frequency of 3.8 kHz and the auditory pavilion around 5 kHz; 2) non-linear, energy transmission through the middle ear, especially in the tympanic membrane where it is most efficient at the frequencies of 1–5.5 kHz; 3) acoustic reflex only attenuates intense sounds that have frequencies below 2 kHz, and is most efficient below 1 kHz.The use of ginseng attenuated the hydrogen peroxide-induced oxidative stress and apoptosis in human neuroblastoma cells, but only animal studies were carried out to observe the effect of ginseng on NIHL.44In view of the results found, it is suggested that antioxidants may have otoprotective effects by reducing the harmful effects of reactive oxygen species on the cochlea and, consequently, on sensorineural hearing loss.Ginseng was the antioxidant that prevented auditory threshold worsening in the 4-kHz but not at the 6-kHz frequency in patients with sensorineural hearing loss caused by exposure to high levels of sound pressure. There was no improvement in the thresholds with vitamin E supplementation.The authors declare no conflicts of interest.