On the behavioral level, we found a significant interaction of memory load and listening condition; this was, however, similar for both groups. Under low, but not high memory load, listening condition significantly influenced task performance. Similarly, under easy but not difficult listening conditions, memory load had a significant effect on task performance. On the neural level, as measured by the BOLD response, we found increased responses under high compared to low memory load conditions in the left supramarginal gyrus, left middle frontal gyrus, and left supplementary motor cortex regardless of hearing ability. Furthermore, we found increased responses in the bilateral superior temporal gyri under easy compared to difficult listening conditions. We found no group differences nor interactions of group with memory load or listening condition. This suggests that memory load and listening condition interacted on a behavioral level, however, only the increased memory load was reflected in increased BOLD responses in frontal and parietal brain regions. Hence, when evaluating listening abilities in elderly participants, memory load should be considered as it might interfere with the assessed performance. We could not find any further evidence that BOLD responses for the different memory and listening conditions are affected by mild to moderate age-related hearing loss.Age-related hearing loss has been associated with increased recruitment of frontal brain areas during speech perception to compensate for the decline in auditory input. This additional recruitment may bind resources otherwise needed for understanding speech. However, it is unknown how increased demands on listening interact with increasing cognitive demands when processing speech in age-related hearing loss. The current study used a full-sentence working memory task manipulating demands on working memory and listening and studied untreated mild to moderate hard of hearing ( Age-related hearing loss (presbyacusis) affects a large part of the older population and encompasses the decline of hearing ability in higher frequencies , 2. AlonThis listening effort may bind cognitive resources that might otherwise be available for concurrent cognitive requirements when processing spoken language. Even in young, normal-hearing listeners, it was shown that imposing additional memory load on a sentence intelligibility task changed the pupil dilation response, which can be an indicator of listening effort . FurtherAdverse listening conditions require people to use more resources which result in the recruitment of additional brain areas, primarily in the frontal cortex. Several studies found increased neural responses in areas including the cingulo-opercular network, the inferior frontal cortex, the insula, and the middle frontal gyrus during difficult listening conditions –19. SimiHence, the aim of this study was to investigate how increased demands on working memory interact with increased demands on listening effort in hard of hearing and normal-hearing participants. Subjects with mild to moderate untreated age-related hearing impairment and age-matched participants with normal hearing were studied with functional magnetic resonance imaging (fMRI). The main fMRI task was a verbal working memory task using full sentences. Here, we employed a 2 × 2 design with varying memory load (high or low) and listening condition (difficult or easy). Participants were asked to listen to two sentences and either recognize a word from the last sentence (low load) or to compare whether a noun or a verb was the same in both sentences (high load). This allowed for a rather naturalistic setting to measure working memory, as information had to be extracted from full-length sentences. We expected larger drops of performance in hard of hearing participants under either high memory load or difficult listening conditions, meaning that the performance difference between easy and difficult listening conditions under high memory load is greater in the hard of hearing as compared to the normal hearing. On the neural level as measured by the BOLD response, we hypothesized (1) stronger engagement of frontal brain areas, including the cingulo-opercular network, the inferior frontal and premotor cortices, the insula, and the middle frontal gyrus, when listening conditions are more difficult ; and (2)n = 19 did not exceed the threshold of 25 dB and were therefore classified as normal hearing, and n = 20 participants were classified as hard of hearing (M = 64.9 (SD = 5.67) years and M = 63.32 (SD = 6.13) years, respectively. All participants were screened for MRI contraindications. The subjects were right-handed, native German speakers, had normal or corrected-to-normal vision, and had no history of neurological or psychological disease. Furthermore, participants had no experience with hearing aids. The project was approved by the ethics committee of the Carl von Ossietzky University Oldenburg (“Kommission für Forschungsfolgenabschätzung und Ethik”) and adhered to the Declaration of Helsinki [http://AsPredicted.com/ on the 27th of March 2019 and has the document number 21386.For this study, we recruited two age-matched groups of participants with either age-appropriate hearing abilities or mild to moderate age-related hearing loss. In total, 43 participants between the age of 50 and 75 years took part in this study. Four participants had to be excluded from the analysis due to movement artifacts in the MRI (>3 mm). Audiometric assessment and classification into hard of hearing and normal-hearing participants were executed by trained staff. Normal hearing abilities were classified as a mean value of 25 dB or better in pure tone audiometry in the frequencies from 2000 to 8000 Hz  All part hearing . ParticiHelsinki . Particihttps://osf.io/rs62e/. The order of the four conditions and the rest condition was randomized once in such a way that no two rest conditions would follow each other. This order was then presented to all participants in the same manner. Each sentence pair was assigned to one condition and would only appear once . Sentences within the conditions were shuffled across trials for each participant. Hence, the order of the conditions was the same for each participant, but the order of the sentences that appeared within a condition was shuffled. Rest conditions lasted 13 seconds and consisted of a white fixation cross on a grey background. Task trials also had a duration of 13 seconds. In total, 84 trials were performed, leading to a task duration of approximately 18 minutes. After the measurement, participants were asked to rate the difficulty of the task conditions on a four-point scale .Within the MRI, participants performed a verbal working memory task. The stimulus material consisted of sentences from the Oldenburg Audiologically and Linguistically Controlled Sentences  read by http://www.neurobs.com/). The task was presented via a projector  on a screen, which participants could see through a mirror attached to the head coil. Auditory stimulation was achieved via MRI-compatible headphones  while active noise cancelling was enabled to filter out high-frequency gradient switching noise. Two buttons of MRI-compatible response pads served to record the participants' responses .The task was programmed using Presentation® software   were admTo further characterize our sample, several additional listening tests were administered. To assess their understanding of speech-in-noise, participants completed the OLSA twice, once outside the scanner with speech noise (SNR) and once inside the scanner with MRI noise (dB). Listening effort was captured with the Adaptive Categorical Listening Effort Scaling (ACALES) test , an adap3, number of slices = 224, matrix = 320 × 320, field of view = 240 × 240 mm). Resting state and diffusion tensor imaging data were acquired within a larger project on hearing impairment and are not presented here.MRI data were acquired using a 3 Tesla Siemens Magnetom Prisma scanner  and a 20-channel head coil. Participants wore hearing protection and MRI-compatible active noise-cancelling headphones. The remaining space was filled with foam pads to minimize head movement and to keep the headphones in position. Functional images with a blood oxygen level dependent (BOLD) contrast were created with an echo planar imaging (EPI) sequence (repetition time (TR) = 1800 ms, echo time (TE) = 30 ms, flip angle = 75°, voxel size = 3 mm, slice thickness = 4 mm, number of slices = 33, field of view = 192 × 192 mm). For the verbal working memory task, 635 images were collected. Additionally, a T1-weighted structural image was acquired using a magnetization prepared rapid gradient-echo (MPRAGE) sequence  including the whole length of the 13-second trial. Low-frequency noise was removed with a temporal high-pass filter at 128 seconds. Temporal autocorrelations were corrected using an autoregressive model of the first order. The parameters of the GLM were estimated using a restricted maximum likelihood approach. The four conditions of the verbal working memory task as well as the rest condition were entered into the model as regressors of interest. The six movement parameters obtained during preprocessing were entered as nuisance regressors. On the first level, contrast images for each subject were calculated for each condition  against the rest condition. At group level, a full factorial model using the contrast images created on the first level was performed. The two groups were entered as a factor as well as the task conditions of high/low load and easy/difficult listening, yielding a 2 × 2 × 2 model. We analyzed the main effects of memory load, listening condition, and group, as well as interactions on a whole brain level using cluster-based corrections for multiple comparisons . Additionally, specific contrasts for memory load  and for listening condition  for hard of hearing compared to normal-hearing participants were computed using a working memory mask including dorsolateral prefrontal and superior parietal cortex, and an auditory effort mask including the cingulo-opercular network, the inferior frontal and premotor cortices, the insula, and the middle frontal gyrus. Results were projected onto a surface rendering for better visibility using SPM12's render option and an example surface from SPM12. To provide evidence for the absence of BOLD response differences between groups, we computed an additional Bayesian independent sample T-test with default prior option (Cauchy distribution) comparing beta values between both groups. This data analysis was performed in JASP .MRI data were preprocessed and analyzed statistically using Matlab R2016a  and SPM12 . Preprocessing of the functional images included a realignment estimation, coregistration to the structural image, normalization into MNI standard space using parameters obtained during structural image segmentation, and, finally, smoothing using an 8 mmt-tests. When applicable, a Mann–Whitney U-test was used instead.All behavioral data were analyzed using SPSS 25 . Behavioral data were first controlled for normal distribution using a Kolmogorov-Smirnov test. The performance score was entered into an ANOVA with factors group, listening condition, and memory load as independent variables, the same was done for the difficulty ratings for each condition. Sum scores of the MoCa (cognitive abilities), multiple choice word test , listening effort questionnaire, and GDS (depression) were evaluated. For executive functioning, we used the Stroop Interference score as well as the sum of errors in the Intra-Extradimensional Set Shift task during within- and between-set switches. Further, the difference in time needed to complete Trail 5 and Trail 1 on the CTMT (cognitive flexibility) was evaluated. For the hearing measures, the mean hearing loss in the frequency range from 2000 to 8000 Hz was used, as well as the SRT measured by the OLSA. In the ACALES, the mean SNR at every rating stage was used. All cognitive and hearing tests were evaluated for group differences using two-sample t(37) = 2.06, p = 0.046, and d = 0.68. Results for the cognitive tasks CTMT, MoCa, Stroop, WST, and Set Shifting can be found in Normal-hearing and hard of hearing participants did not differ in age, handedness, or cognitive capabilities in any task or subtask. Neither group exhibited depressive symptoms. Only in the verbal intelligence test (WST) normal-hearing participants performed significantly better than hard of hearing participants, t(37) = −9.91, p < 0.001, d = −3.25. Hard of hearing participants exhibited a significantly worse speech-in-noise reception outside the scanner  than normal-hearing participants, U = 6, p = 0.011; however, the groups did not differ in their threshold when the same test was performed inside the scanner . There was no group difference in subjectively experienced daily listening effort. In the ACALES, both groups differed significantly at twelve of thirteen stages of listening effort rating except for the condition of “high effort” (t(37) = 2.17, p = 0.035, as well as for SNRs rated as “medium effort,” t(37) = 2.51, p = 0.016  = 8.85, p = 0.003, η2 = 0.056) as well as under difficult compared to easy listening conditions  = 10.44, p = 0.002, η2 = 0.066). Additionally, participants' performance was influenced by the listening condition when memory load was low, but not when memory load was high  = 6.11, p = 0.015, η2 = 0.040, Figures Participants performed significantly worse under high compared to low memory load conditions,  = 80.97, p < 0.001, η2 = 0.354). However, there was neither a difference in the rating of the memory load conditions nor in ratings between the groups , memory load (high vs. low), and listening condition (easy vs. difficult). The results are listed in A regression analysis modelling the sample as one group with hearing loss as measured by the mean PTA in the higher frequencies as a regressor also showed no significant association of BOLD response and hearing impairment.x = −44, y = 24, and z = 30) and for the superior temporal gyrus for the easy versus difficult listening condition . The Bayesian independent samples T-test with beta values showed evidence for the null hypothesis in all brain regions , i.e., no difference between hard of hearing and normal-hearing participants in BOLD responses , memory load (high or low), and listening condition (difficult or easy). We expected larger drops of performance in hard of hearing participants under either high memory load or difficult listening conditions compared to normal-hearing participants. On the neural level, we hypothesized that BOLD responses in hard of hearing compared to normal-hearing participants are (1) increased in frontal brain areas, including the cingulo-opercular network, the inferior frontal and premotor cortices, the insula, and the middle frontal gyrus, when listening condition is difficult, and (2) increased in working memory-related areas, especially dorsolateral prefrontal and superior parietal cortex, under high memory load condition.Our results on the behavioral level indicated that participants' performance was influenced by the listening condition only under low memory load, leading to a better performance when listening conditions were easy. Additionally, only under easy listening conditions memory load influenced the performance, leading to a decrease when memory load was high. This effect was, however, similar in hard of hearing and normal-hearing participants. On the neural level, participants showed increased BOLD responses in working memory areas in high compared to low memory load conditions and in auditory regions in easy compared to the difficult listening conditions. We found no significant differences in BOLD responses between the groups, and there were no significant interactions between any factors or factor levels.The behavioral data provide evidence that challenges on memory load or listening impair task performance and interact with each other. Participants performed worse under high load as well as under difficult listening conditions. When investigating the interaction of memory load, listening condition, and group, there was a significant interaction effect of listening condition and memory load, but no interaction with the factor group. In both groups, the listening condition had an impact under low but not high memory load. Similarly, memory load modulated performance only under easy listening conditions. In other words, only when either memory load, listening condition, or both were difficult, performance was significantly worse. This interaction suggests that regardless of group, under more difficult conditions, cognitive resources are bound by either the stimulus perception or the solving of the task, which leads to a decline in performance. This interaction was significant for all participants; therefore, normal-hearing older adults are affected to the same extent as hard of hearing individuals by an increased working memory load or difficult listening condition. These were surprising findings, since we expected that hard of hearing participants in contrast to their normal-hearing peers would show higher drops in performance between high and low memory load conditions when listening was difficult as well as between easy and difficult listening conditions when memory load was high. An explanation for the lacking group effect might be that the difficult listening situation within the MRI resembles listening conditions to which the hard of hearing participants have already adapted to due to their decreased auditory input. This may explain why the sound level necessary to obtain 80% SRT during scanning did not differ significantly between the groups, which was also the case in our previous study . Hence, To sum up, our results support the theory that listening to speech in noise binds resources that could be used for other tasks , 34. HenTo investigate differences in BOLD responses, we performed a full factorial model with the factors group , memory load (low vs. high), and listening condition (easy vs. difficult). When investigating the effect of memory load, we found increased responses in several frontal and parietal areas. Areas with significantly increased BOLD responses under high compared to low memory load were found in the left middle frontal gyrus, the left supplementary motor cortex, the left supramarginal gyrus, and in the right cerebellum. The left middle frontal gyrus is a brain region that shows increased activity when more items need to be maintained in working memory , 36 and These results suggest that neural activity as measured by the BOLD response of effortful speech perception and cognitive control due to higher demands on verbal working memory is increased, which is surprising as participants did not rate the high memory load condition as significantly more difficult than the low memory load condition. This highlights the importance of using neuroimaging measures of cognitive effort that do not rely on self-report to gain insight on listening in noise in the elderly, especially regarding age-related hearing loss. We conclude that participants responded to higher working memory load with increased BOLD response amplitudes in areas that aid speech perception to meet the increased demands of the task.Our fMRI data also showed a main effect of listening condition. Increased BOLD responses were rooted in the contrast of easy compared to difficult listening condition and comprised the left and right superior temporal gyrus. These areas are associated with speech perception and production , 47. HenWe found no significant differences between hard of hearing and normal-hearing participants in brain activation patterns during a verbal working memory task. The additional Bayesian analysis provided evidence for the null hypothesis as well. To rule out noisy data as an explanation for our null effect, we calculated the SNR of the measurement using the MRIQC tool . The SNRAn explanation for the absence of group effect may be that the verbal working memory task generally was rather difficult, even in the easier conditions, and therefore was not sensitive enough to distinguish between normal-hearing and hard of hearing participants. A study by Cardin et al.  found leThis is the first study that provides results from a verbal working memory task that uses real-life, full-sentence stimuli in a sample of mild to moderate hard of hearing participants. Even though using sentences drastically increases task difficulty, we believe that it can provide valuable insights into a more natural way of language processing and mimic cognitive challenges that hard of hearing elderly often experience in daily life. There was a significant interaction of listening condition and memory load, whereby performance was only influenced by the listening condition under low memory load conditions, and similarly by memory load only under easy listening conditions. We found increased BOLD responses in high compared to low memory load conditions as well as to easy compared to difficult listening conditions. Under high memory load, frontoparietal regions were recruited regardless of hearing impairment; however, there was no additional recruitment of these regions under difficult listening conditions nor an interaction of memory load and listening condition. Increased BOLD responses in temporal regions in the easy listening condition are likely due to the loudness of the stimuli. We conclude that memory load and listening condition interacted on a behavioral level, whereas our task-imposed challenges interacted with verbal working memory, but not listening effort, on the neural level as measured by the BOLD response. The absence of group differences may indicate that the mild to moderate stage of hearing-loss may not yet be advanced enough to elicit significantly different response patterns from normal-hearing participants. BOLD responses for the different memory and listening conditions may only be altered in severe stages or longer durations of age-related hearing loss.


Introduction: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a complex autoimmune disease caused by dysregulated response to not fully recognized antigens. Some association between CIDP and inflammatory bowel disease (IBD) has been reported, but the exact pathophysiological links of these disorders are not well understood.Aim of the Study: To evaluate fecal calprotectin as a biomarker of gut inflammation in CIDP patients without IBD.Methods: Fifteen patients with CIDP and 15 healthy controls were included in the study. The CIDP diagnosis was based on the EFNS/PNS criteria. The occurrence of bowel symptoms was assessed based on a questionnaire. The quantitative evaluation of fecal calprotectin level was performed by the ELISA test.Results: The fecal calprotectin level (μg/g) expressed as median along with the lower and upper quartiles [25Q–75Q] was significantly higher in CIDP patients compared to the controls: 26.6 [17.5–109.0] vs 15.6 [7.1–24.1], p = 0.0066. Abnormal fecal calprotectin level (>50 μg/g) was found in 33% of all CIDP patients and in none of the control subjects. The patients with abnormal fecal calprotectin level did not differ from the rest of the study group regarding the neurological status. The most common bowel symptoms reported by CIDP patients included constipation (33%), feeling of incomplete evacuation (33%), bloating (27%), and alternating bowel movement pattern (27%).Conclusion: In one-third of CIDP patients the signs of gut immune system activation have been observed. This finding may be associated with CIDP pathogenesis and induction of autoimmune response as well as concomitant dysautonomia with gastrointestinal symptoms. Chronic inflammatory demyelinating polyneuropathy (CIDP) is characterized by symmetrical, proximal and/or distal paresis as well as sensory loss developing over a period of at least 8 weeks . CIDP isCurrently, there is a growing recognition of the role of gut inflammation, gut dysbiosis and altered intestinal permeability in the pathogenesis of different autoimmune diseases . Since tFecal calprotectin, the main protein produced by activated monocytes and neutrophils in the inflamed gut tissue, serves as a key marker for the level of intestinal inflammation . It is rThe study was conducted in 15 patients with CIDP  hospitalized at the Department of Neurology at Wrocław Medical University (Poland) and 15 healthy controls . The CIDP diagnosis was based on the EFNS/PNS criteria . Data onThe protocol of this study was approved by the local Ethics Committee (KB-491/2017). A written informed consent in accordance with the Declaration of Helsinki was obtained from all participants prior to the study enrollment.U test was applied to compare differences in fecal calprotectin levels between the groups.Non-parametric statistics were used and results are expressed as median along with the lower and upper quartiles [25Q–75Q]. The Mann-Whitney p = 0.0066 . The mean protein level in cerebrospinal fluid (CSF) amounted to 94 mg/dl (range 40–231 mg/dl). The fecal calprotectin level (μg/g) was significantly higher in CIDP patients compared to the controls: 26.6 [17.5–109.0] vs 15.6 [7.1–24.1], = 0.0066 . ApplyinThe most common bowel symptoms reported by the CIDP patients included abnormal bowel habit (67%), feeling of incomplete evacuation (33%), bloating (27%), and abdominal pain (7%). Normal bowel movement pattern was observed only in 33% of the studied CIDP patients. Two-third of them experienced changes in stool consistency and frequency such as constipation (33%), alternating bowel movement pattern (27%), and diarrhea (7%).Comparing basic data of the patients with normal and increased fecal calprotectin level presented in p = 0.0066).The results of the present study indicate that one-third of CIDP patients without any recognized bowel disease are characterized by the signs of gut immune system activation reflected by the increased fecal calprotectin level. Although the median fecal calprotectin level in all studied CIDP patients was still within the normal range  it was significantly higher compared to that in the controls . In typical CIDP proximal and distal nerve segments are involved, and humoral immunity seems to dominate, but patients with nodo-paranodopathy have more significant electrophysiological changes, and they are resistant to intravenous immunoglobulin treatment .While the origin of CIDP still remains not fully recognized, there is a growing understanding of the role of gut dysbiosis together with genetic predisposition and environmental factors  in the development of autoimmune diseases . The sugThe modulation of the gut microbiota composition has been found to exert therapeutic effect in many autoimmune disorders including IBD , type 1 The majority of CIDP patients in the current study suffered from abnormal bowel habit, bloating, and some anorectal sensory disturbances manifesting as feeling of incomplete evacuation. The reported gastrointestinal symptoms might be associated with the gut immune system activation potentially related to concomitant gut dysbiosis. However, these symptoms might also result from autonomic dysfunction which is common in CIDP . The preThe small number of subjects included in this pilot study is one of the main limitations of the analysis. Nevertheless, the obtained results highlight a novel research field associated with close interactions between the gut immune system and inflammatory peripheral neuropathies. Moreover, since there is evidence that a number of immunomodulators, including corticosteroids, may reduce calprotectin expression , it woulIn conclusion, the results of the current study confirmed signs of the gut immune system activation in a significant part (30%) of CIDP patients that may be associated with the pathogenesis of the disease and induction of autoimmune response as well as with gastrointestinal symptoms frequently observed in CIDP patients. Further studies aimed at elucidating the link of gut inflammation in CIDP may support immunomodulatory therapeutic approach including the gut microbiota modification.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 the Ethics Committee at Wrocław Medical University, Wrocław, Poland (KB-491/2017). The patients/participants provided their written informed consent to participate in this study.MK and AM designed the study and wrote the manuscript. ED collected the samples. SB was involved in writing and revising the manuscript. All authors were involved in collecting and interpreting the data and approved the final version of the article.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.


Introduction: Smoking is a well-recognized risk factor for many health issues; however, its association with hearing loss has been a debate. Some studies have shown a positive association while others did not. In this study, we aim to identify the effect of cigarette smoking on hearing in our population.Methods: This cross-sectional study was conducted in a tertiary care hospital in Pakistan from August 2020 to March 2021. Five hundred male smokers (n = 500), with a history of smoking for more than three years between the ages of 21 and 50, were enrolled in the study via consecutive convenient non-probability sampling after informed consent. Five hundred male non-smokers (n = 500) were enrolled as a reference group. Audiometry was performed in a soundproof room.Results: The hearing levels in audiometry were significantly higher in smokers compared to non-smokers . Participants who had been smoking for more than 10 years had higher hearing levels in the audiometry test compared to the participants with less than 10 years of smoking history .Conclusion: In this study, smokers were associated with greater loss in hearing compared to non-smokers. In addition to other adverse events associated with smoking, smokers should be counselled about hearing loss related to it. Among the five basic senses humans have, hearing is one of the most important tools for social connectivity and communication. As per World Health Organization (WHO), it has been found that hearing loss is one of the greatest causes of human disability with a prevalence of over 5% of the worlds’ population, approximating up to 250 million people ,2. DisabSmoking is a well-recognized risk factor for many health issues, such as lung cancer and cardiovascular diseases; however, its association with hearing loss has been a debate. Some studies have shown a positive association while others did not. Several theories have been put forth to explain the effect of nicotine on the auditory system, including vasospasm of the small blood vessels of the inner ear, ototoxicity, increased blood viscosity and cochlear ischemia ,4. PassiThere is very limited data available that study the impact of smoking on the hearing level. In this study, we aim to identify the effect of cigarette smoking on hearing in our population. By identifying smoking as a risk factor for hearing loss, we can counsel patients about the implication of smoking on hearing.This cross-sectional study was conducted in a tertiary care hospital in Pakistan from August 2020 to March 2021. Five hundred male smokers (n = 500), with a history of smoking for more than three years between the ages of 21 and 50, were enrolled in the study via consecutive convenient non-probability sampling after informed consent. Five hundred male non-smokers (n = 500) were enrolled as a reference group. Participants with age more than 50 years, pre-existing ear deformity, hypertension, diabetes and patients on ototoxic drugs were excluded from the study, as all of them are known risk factor for hearing loss. Ethical review board approval was taken before enrolment of the patients.Patients’ characteristics including age, duration of smoking, body mass index (BMI), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were noted in a self-structured questionnaire. The audiometry was performed in a soundproof room. Trained otolaryngologist technicians performed tests and collected data at different frequencies for each ear at six different frequencies, i.e. 0.5, 1.0, 2.0, 3.0, 4.0, and 6.0 kilohertz (kHz). The final hearing level was taken as the mean of hearing levels of both ears.Statistical analysis was done using Statistical Package for Social Sciences® software version 23.0 . Categorical data such as age distribution was presented as frequency and percentage. Numerical data such as BMI and hearing level were presented as mean and standard deviation. t-Test and Chi-square were applied as appropriate. A p-value of less than 0.05 meant that the difference between the groups is significant and the null hypothesis is void.The distribution of age group, BMI, SBP, and DBP was comparable between the two groups Table .The hearing levels in audiometry were significantly higher in smokers compared to non-smokers   Table .The result of our study highlights the effect of cigarette smoking on hearing levels. Moreover, higher audiometry tests were observed in participants having a smoking history of more than 10 years compared to the ones of less than 10 years. Hence, indicating that duration of smoking has a major impact on hearing levels.Several studies have been conducted to demonstrate the association of cigarette smoking with hearing loss. Our findings are in line with the findings of a large-scale cohort study conducted among a Japanese working population, which also demonstrated the association between smoking and hearing loss . SimilarThe scientific rationale of this study is to provide strong evidence to support that smoking is a risk factor for hearing loss. It further emphasizes the need for smoking cessation to delay the developments of hearing loss. Moreover, it highlights the need for counselling or help from a doctor or therapist. This type of counselling may include information about the effects of smoking on the body, advice on ways to quit, and other assistance that may improve the chances of quitting. Awareness of triggers for smoking can be gained in therapy and alternative behaviours can be explored, both of which may help break the habit of smoking. It further helps to prevent its complications and to improve the quality of life.In this study, smoking was associated with increased hearing loss in young and middle-aged males. Hearing loss was also directly proportional to the duration of smoking. In addition to other adverse events associated with smoking, smokers should be counselled about hearing loss related to it. Smokers should have their hearing tested frequently for timely intervention. Counselling about the adverse event of smoking may help prevent hearing loss in smokers.


NDP gene, presenting as congenital blindness followed by later onset of hearing loss. Protecting patients from hearing loss is critical for maintaining their quality of life. This study aimed to understand the onset of pathology in cochlear structure and function. By investigating patients and juvenile Ndp-mutant mice, we elucidated the sequence of onset of physiological changes  and determined the cellular, histological, and ultrastructural events leading to hearing loss. We found that cochlear vascular pathology occurs earlier than previously reported and precedes sensorineural hearing loss. The work defines a disease mechanism whereby early malformation of the cochlear microvasculature precedes loss of vessel integrity and decline of endocochlear potential, leading to hearing loss and hair cell death while sparing spiral ganglion cells. This provides essential information on events defining the optimal therapeutic window and indicates that early intervention is needed. In an era of advancing gene therapy and small-molecule technologies, this study establishes Ndp-mutant mice as a platform to test such interventions and has important implications for understanding the progression of hearing loss in Norrie disease.Norrie disease is caused by mutation of the   NDP) gene (Norrie disease is an X-linked disorder caused by mutations in the Norrie disease pseudoglioma (DP) gene . It resuDP) gene . Norrie DP) gene –5. ThereIn contrast to the congenital nature of the blindness, the childhood/adult onset of hearing loss does provide a possible opportunity to intervene and prevent it from happening. To achieve this, we must first understand the sequence of events underlying the progression of hearing loss in Norrie disease. Given that Norrie disease is rare and it is difficult to examine cochlear pathology prior to death, investigations into the events leading to hearing loss in patients have been limited. In 1990, Nadol et al. described observations from postmortem tissue of a 77-year-old Norrie disease patient who suffered from hearing loss. They reported effects in the whole cochlea with a severely atrophied stria vascularis , loss of sensory hair cells throughout the cochlea, and dense deposits of fibrous tissue around degenerating spiral ganglion neurons  . ClinicaNdp gene (tm1Wbrg/YNdp) display an ocular phenotype consistent with that of patients with Norrie disease, albeit less severe (tm1Wbrg/YNdp mice examined histology and hearing loss (by ABRs to pure tone bursts) in aging mice from 3 to 15 months but did not analyze auditory function at earlier stages. The tm1Wbrg/YNdp mice showed progressive hearing loss and pathological changes in the cochlea including enlarged blood vessels in the stria vascularis, loss of hair cells, and degeneration of the spiral ganglion  receptor, which, together with the coreceptor LDL receptor–related protein 5 (LRP5) and the membrane protein tetraspanin 12 (TSPAN12), regulates vasculature development in the retina via canonical WNT signaling , much earlier than the onset of hearing abnormalities, in We studied available audiograms from 6 patients with Norrie disease and hearing loss. Onset of hearing loss was detected at the ages of 3 years (N01), 6 years (N05), and 8 years (N07). For the patients whose hearing loss was detected at the ages of 4 years (N08), 5 years (N04), and 35 years (N06), we had no earlier audiograms, although N04 passed the newborn hearing screen. Hence the onset of hearing loss could have been earlier.In another patient (N08), for whom audiograms were available for 14 years (ages 4–18 years), hearing loss was present at the age of 4 years . The lowThe longest duration of follow-up of an individual patient (N07) was 30 years (6–36 years of age) . Normal The hearing loss was asymmetric at onset in 3 of 6 patients with a trend toward the same flattish configuration over time. The degree of hearing loss as a function of time followed a similar trajectory between patients, both at low frequencies 250 Hz;  and at mThese clinical data showed that hearing loss may affect high or low frequencies first and it then progresses to other frequencies . This tyNdp-KO). ABRs provide an objective measure of auditory function and were used here to assess whether the Norrie disease mouse mutant showed abnormalities in auditory function at 1 month (juveniles) and 2 months old (adults)  , with elevated thresholds apparent for clicks and 6- to 18-kHz tones , but not for higher-frequency stimuli  . Anesthe 0.4540) . By 2 mo stimuli .Ndp-KO compared with WT at 1 month  (https://doi.org/10.1172/jci.insight.148586DS1). However, this difference was not seen in the 2-month-old group     (Ndp-KO compared with WT at 1 month (data not shown).Further examination revealed that the click-evoked ABR wave I was significantly reduced in amplitude in  0.6148) . Convers 0.2588)  but was 0000001) . The latparison) , E–H. A Ndp-KO mice compared with WT, and the wave I deficit was only found in the 1-month-old group. Adult-like auditory responses are normally achieved by the end of the first postnatal month  , with thresholds showing elevations across all f2 frequencies tested from 6 to 30 kHz , the slope of DPOAE growth was comparable for each f2 stimulus in each age group (We next assessed OHC function at 1 and 2 months using distortion product otoacoustic emissions (DPOAEs) . At 1 mo 0.1326) . By 2 moo 30 kHz  comparedNdp-KO mice at both ages . At 1 month, EP was significantly reduced from 125.75 ± 9.62 mV in WT to 109.96 ± 14.47 mV in Ndp-KO mice, but at its mean value of 110 mV, there would be little effect on cochlear function expected   , whereas the EP of WT mice was not significantly changed . EP reduction in the Ndp mutants therefore preceded the abnormal OHC function (DPOAEs) and elevated ABR thresholds.As endocochlear potential  is essential for sound transduction, we assessed whether EP deviated from normal levels at 1 and 2 months. A rise in EP can be first measured by P6  and then0092067) . At 2 mo0019031) , a levelNdp-KO mice at the end of the first postnatal month, we first examined the SGNs to assess whether there was a corresponding loss of these primary afferent neurons. A previous study reported loss of SGNs from the apical cochlear region in 15-month-old Ndp-KO mice , we used immunostaining for the neuronal intermediate filament Nf200 (Ndp-KO mice (P = 0.028), not in the basal and middle regions . OHC loss was highest in the middle region at four-eighths of the length of the organ of Corti from apex to base, corresponding to approximately 16–21 kHz . By 2 months, substantial degeneration of the OHC had occurred, which distorted the morphology of the organ of Corti, hampering identification of individual viable OHCs by phalloidin staining, while the IHCs remained intact (data not shown). Labeling of hair cell bodies with anti–myosin VIIA antibody confirmed the integrity of IHCs in Ndp-KO at 2 months and allowed identification of surviving individual OHCs  by 2 months in the Ndp-KO   whole mounts of the organ of Corti were stained with phalloidin or with anti–myosin VIIA antibody and DAPI to delineate cell morphology and nuclei and to quantify hair cell degeneration  . OHC losIn summary, at 2 months, but not at 1 month, apical low-frequency functional deficits were detected by ABRs (6–18 kHz). Regional OHC loss and abnormally elevated DPOAE thresholds affecting a wider low- to mid-frequency range (up to 30 kHz) similarly progressed from near normal at 1 month to a marked pathology by 2 months. Considered together, these findings suggested that OHCs are initially functional and that degeneration may be secondary to an earlier insult. Our observation that EP was significantly lower than that of the WT at both 1 and 2 months indicated that there could be an early developmental malformation and dysfunction of the lateral wall cochlear tissue, which is responsible for generation and maintenance of EP.+ into the endolymph, producing the positive EP. The source of this K+ is the underlying syncytial cell layers, composed of intermediate cells, basal cells, and fibrocytes, which form a single syncytium due to the high density of gap junctions between them  in WT  and 81.6 ± 10.5 μm2 in Ndp-KO . The stria vascularis was also thinner; the mean distance from the luminal surface to the interface between basal cells and spiral ligament at 2 months was 32.4 ± 0.3 μm in WT  and 29.4 ± 0.5 μm in Ndp-KO . No differences in morphological features were identified after direct examination of endothelial tight junction structures from both WT and Ndp-KO   , G–L.Some marginal cells also showed abnormalities: there was a loss of electron density; the extensive basolateral infoldings of the cell body were reduced, giving the cell a more smoothly rounded cell body; and the nucleus had changed shape at 1 month  and at 2Ndp-KO and WT : al cells ; and Plvectively –32 , a critical component of endothelial tight junctions that control pericellular permeability, is also affected in  vessels , 40. We  vessels . At P10,  and desmin (pericytes). The total percentage area of vessels covered by pericytes was compared between Ndp-KO and WT   , C and Eigament)  comparedTogether these data demonstrate an early abnormal organization of pericytes within the developing cochlear microvasculature and progressive remodeling and disruption of tight junctions, which are likely to cause the later pathologies.Ndp-KO model of Norrie disease. Based on our observations of a strial defect and reduced EPs as early features, the hearing loss in Norrie disease is probably best classed as a strial or metabolic defect  of pathological lesions occurring within the auditory system of the c defect , which lOur review of hearing loss in a small set of patients with Norrie disease showed in all but 1 child that the hearing loss was mild to moderate at onset, but in a single 5-year-old, a moderate to profound hearing loss was detected. This indicates that in some children, the progression of hearing loss can be accelerated. The hearing loss affected low or high frequencies first in different individuals, and there was no indication of OAE abnormality in 1 child in whom this test was done when hearing loss was mild. Over time the hearing loss in the patients with Norrie disease progressed to be bilateral and flattish. Hearing loss was documented in all children before the age of 11 years, and as early as 3 years of age, where audiograms were available. There are several previous reports suggesting that a flattish audiogram shape is likely to indicate a strial defect, and it is interesting that the audiograms of these 6 Norrie patients have flattish shapes  , 43.Ndp loss of function in the largely C57BL/6 genetic background, whereas the earlier study analyzed the effect on a more mixed background  outcrossed for 2 generations to CBA/CaJ and found impairments at all different frequencies at 3–4 months progressing to relatively flat profound loss by 15 months  compared with other cell types in the lateral wall . Animal studies were carried out after University College London and King’s College London Ethics Review approval and in accordance with UK Home Office regulations and the UK Animals (Scientific Procedures) Act of 1986 under UK Home Office license.The study was conceptualized by MBG, JCS, WB, VP, DB, and AF. Investigation was carried out by VP, DB, NJI, LAA, and AF. Methodology was developed by VP, DB, NJI, AP, KES, DAM, DJ Jafree, DAL, AAY, DJ Jagger, AF, and JCS. Data analysis and interpretation were done VP, DB, NJI, AP, WP, KES, YCL, KPS, DJ Jagger, AF, WB, and JCS. Resources and funding were acquired by MBG, JCS, and WB. The manuscript was written by VP, DB, NJI, AP, AF, and JCS. All authors provided critical feedback and helped shape the research, analysis, and manuscript. The final manuscript was approved by JCS.


Introduction: Chronic suppurative otitis media (CSOM) is a chronic infection of the middle ear cleft with a permanent perforation resulting in mucopurulent discharge and may include otalgia or fever, vertigo, hearing loss, and tinnitus. These compromise the quality of life of CSOM patients and affect their social communication and professional life also, which may induce social withdrawal and depression.Materials & methods: This cross-sectional study was conducted at the Department of ENT, Indira Gandhi Medical College & Research Institute (IGMC&RI), Pondicherry, India, from May 2019 to May 2020. CSOM patients fulfilling the inclusion and exclusion criteria were recruited for the study.The association of disease characteristics and hearing loss was evaluated by the Spearman correlation test. Correlation of variables such as age, sex, type of disease, laterality hearing loss type, and severity with respect to depression was done using Chi-square test.Results: One hundred forty-two participants were recruited for this study, the majority being females (65%) the mean age being 44.08 years ± SD 15. The safe type of CSOM (tubotympanic disease) was common among the participants (96%) with unilateral disease (78%) more predominating and left side being most frequently (58%). There was a significant and linear correlation of depression and hearing loss to the duration of the disease. Ears are considered supreme to all other sensory organs as rightly said in couplet 411 of Thirukural: “Wealth of wealth is wealth acquired be ear attent; wealth amid all wealth supremely excellent," the importance of which is not realized until lost. Many diseases and disorders affect the ear and subsequently hearing. Chronic suppurative otitis media (CSOM) contributes a major share to this burden globally both in underdeveloped and developed countries. It is defined as a chronic infection of the middle ear cleft with a permanent perforation resulting in mucopurulent discharge .CSOM presents with a chronically discharging ear for at least four to six weeks, with an antecedent history of recurrent acute otitis media (AOM), traumatic perforation, or insertion of grommets . MalodorThis study is a cross-sectional analytical study. It was done on subjects attending the out-patient department of Otorhinolaryngolgy, at Indira Gandhi Medical College & Research Institute (IGMC&RI), for the treatment of CSOM, from May 2019 to May 2020. Our institute is a tertiary care hospital in the South Indian city of Pondicherry, catering to the needs of the local residents and also from the neighbouring districts of Tamilnadu State. All subjects in the age group of 20 to 50 years diagnosed with CSOM in at least one ear were included in the study. Subjects under the age of 20 and above 50 years were excluded from the study in order to have an otherwise healthy and mature study group. We also excluded subjects with previous history or family history of psychological disorder or on treatment for psychological disorders and those with comorbidities such as diabetes, hypertension, heart disease. Since the study was planned with a questionnaire to be filled by the subjects themselves under supervision of a clinician, we excluded those with educational qualification of <8th standard.Assuming the proportion of CSOM patients having depression as 50% with alpha error as 5%, an error of margin as 9%, and a non-response rate of 10% the minimum sample size was calculated to be 131 based on the formula n=Z2P(1-P)/d2, Where n is the sample size, Z is the statistic corresponding to the level of confidence, P is expected prevalence, and d is precision. The actual sample we achieved was 142. Subjects diagnosed with CSOM fulfilling the inclusion criteria were selected. A detailed history was taken regarding the onset, duration, progression, nature of treatment received so far, and also complications of CSOM if present. The subjects were then assessed clinically for laterality  of disease, type of CSOM, and stage of the disease at presentation. Otoscopy was performed to document the tympanic membrane findings. The subjects then underwent pure tone audiometry to assess the type and degree of hearing loss, the findings of which, were documented for analysis. The subjects were then given a pre-validated structured questionnaire, the Hamilton Depression Rating Scale (HDRS), to be filled under the supervision of a clinician to assess depression. The scores obtained were documented in the proforma. The data was analysed using Statistical Package for Social Sciences (SPSS) version 20 . The association between duration disease, type of disease, CSOM related complications, and hearing loss was evaluated by the Spearman correlation test. A Chi-square test was done to assess significant differences among variables such as age, sex, type of disease, laterality, hearing loss type, and severity concerning depression.One hundred forty-two participants were recruited for this study, the majority being females (65%) and residents of Pondicherry state 81%); the mean age was 44.08 years ± SD 15. The safe type of CSOM (tubotympanic disease) was predominantly observed among the participants (96%) with unilateral disease (78%) more common than bilateral (22%) and the left side was found to be most frequently affected (58%) , a small proportion of the study population, had undergone ear surgeries in the past for CSOM and only two 1%) were cured of the disease, the rest had a recurrence. CSOM related complications were observed in two participants (1%), which were lower motor neuron type of facial palsy and mastoiditis respectively  affected than males Table . The majThe prevalence of CSOM in developing countries is estimated to be 72 per 1000. The expenditure on treating ear infections is estimated to be more than 2 billion dollars in the US every year with a prevalence rate of less than 30 per 1000 ,7.Parikh et al.  in theirDepression is characterized by the presence of depressed mood and/or lack of interest in activities that would usually be pleasurable, with loss of appetite, sleep disorders, feeling of guilt and/or depreciation, and all these lasting for at least two weeks ,9.Depressive disorders are emerging as a significant public health problem not only due to their increasing prevalence but also due to the cost incurred for treating it either directly or indirectly . ProjectDepressive disorders can lead to a lack of work productivity and interpersonal problems are serious consequences of depressive disorders in terms of secondary morbidity . There aNumerous studies have focussed on the association of depression and hearing loss ,16 and aIn CSOM, hearing loss occurs due to two phenomena; one is due to lack of effective conduction of sound waves due to tympanic membrane perforation causing conductive hearing loss, and the other is sensory end organ damage due to toxins and inflammatory mediators causing a mixed type of hearing loss .The hearing loss resulting from CSOM restricts a person’s ability to communicate effectively leading to depression, anxiety, and social withdrawal ,22. HearIt was earlier thought that the depression resulting from hearing loss is because of the physical, mental and financial handicaps. But, of late there are shreds of evidence in the literature that demonstrated that hearing loss can induce plasticity in the excitatory and inhibitory neurotransmitter systems (serotonin) in the central auditory brain regions ,26. The Mehboob et al.  assessedThough the symptoms of depression were observed more among females than males similar to the earlier studies , it was One major limitation observed with the HDRS was that it did not include some of the atypical symptoms of depression. Data on other risk factors which could lead to hearing loss such as the presence of other chronic non-communicable diseases, smoking, chronic noise exposure and ototoxicity was lacking. The financial or socioeconomic status of subjects was also not taken into account. All these factors could possibly affect the subject’s quality of living either individually or together and thus, may lead to depression.We conclude that a long-standing ear disease with persistent discharge and hearing impairment can result in depression. The severity of depression increases proportionately with increasing duration of disease, severity of disease and the degree of hearing impairment. We believe this study will help to deliver better and timely care to curtail the suffering from CSOM and to identify susceptible individuals early in the course of the disease to treat them holistically. We expect that this study will provoke and promote further prospective clinical and biomedical studies on the relationship of CSOM, hearing loss, and depression to determine its aetiopathogenesis.


Resting metabolic rate (RMR) has been examined as a proxy for low energy availability (EA). Previous studies have been limited to adult athletes, despite the serious health consequences of low EA, particularly during adolescence. This study aimed to explore the relationship between RMR and EA in competitive teenage girl runners.Eighteen girl runners  in the same competitive high-school team were evaluated. Each runner was asked to report dietary records with photos and training logs for seven days. Energy intake (EI) was assessed by Registered Dietitian Nutritionists. The runners were evaluated on a treadmill with an indirect calorimeter to yield individual prediction equations for oxygen consumption using running velocity and heart rate (HR). Exercise energy expenditure (EEE) was calculated by the equations based on training logs and HR. Daily EA was calculated by subtracting EEE from EI. The daily means of these variables were calculated. RMR was measured early in the morning by whole-room calorimetry after overnight sleep on concluding the final day of the seven-day assessment. The ratio of measured RMR to predicted RMR (RMR ratio) was calculated by race, age, sex-specific formulae, and Cunningham’s equation. Body composition was measured using dual-energy X-ray absorptiometry. Bivariate correlation analyses were used to examine the relationship between variables.−1 FFM⋅d−1, respectively. RMR reduced linearly with statistical significance, while EA decreased to a threshold level  . Further reduction in RMR was not observed when EA fell below the threshold. There was no significant correlation between RMR ratios and EA, irrespective of the prediction formulae used.RMR, EI, EEE, and EA were 26.9 ± 2.4, 56.8 ± 15.2, 21.7 ± 5.9, and 35.0 ± 15.0 kcal⋅kgThese results suggest that RMR does not reduce with a decrease in EA among highly competitive and lean teenage girl runners. RMR remains disproportionally higher than expected in low EA states. Free-living teenage girl runners with low EA should be cautiously identified using RMR as a proxy for EA change. Energy availability (EA) is defined as the energy obtained from dietary intake after subtracting the energy consumed by exercise training . EA may Since it is difficult to accurately measure EA in practice, reductions in resting metabolic rate (RMR) have been examined as a proxy for low EA –9. SinceLong-distance running is a weight bearing endurance sport wherein low body fat helps in enhancing performance. Accordingly, competitive distance runners likely control their EI , raisingEighteen female teenage runners (15−19 years old) from the same high school team were evaluated from 2015 to 2020. One runner had graduated at the time of measurement but continued to train under the instruction of the same team coach. All participants were Japanese, competitive middle- or long-distance (800−5000 m) runners, with a personal best record of 4 min 43 s ± 14 s and 9 min 58 s ± 31 s for 1500 m and 3000 m races, respectively. During the five-year study period, the team consistently ranked high, won the Prefectural Championship Road Running Relay race three times, and advanced to the relevant national championship. Runners from high schools representing the 47 prefectures of Japan participate in the national championship, and they are considered as the best high school runners. The team had been ranked average in the race.All physical training was organized and supervised by the same coach during the study period, while the diet was left to the discretion of each runner. Some participants lived in the same dormitory; in which case their daily lifestyles were strictly controlled. Training sessions were usually performed twice a day: early in the morning and in the evening. Training comprised jogging, tempo running, and high-intensity interval training. Resistance and agility training was similarly performed almost daily.Training details and diet were regularly recorded by the athletes in their diaries. The maximal running mileage was approximately 100 km per week, and the runners went on intensive training camps for up to three weeks, four to five times a year, where the training intensity, daily training hours, and mileage were substantially increased. No significant abnormalities were observed in the participants following mandatory medical check-ups performed in the high school.The study was conducted without interrupting school events, classes, or scheduled training programs, and without modifying the diet of the participants. Particularly, the days requiring an overnight stay at the laboratory were carefully chosen, so as not to affect daily exercise training. Consequently, the day of RMR measurement was set for a previously planned rest day, free from exercise training, which was mostly Sunday, and the last exercise training was scheduled on the morning of the day before the RMR measurement. This was done to secure at least 17 h of abstinence from exercise training for the measurement of RMR. This met the American Dietetic Association’s recommendation on best practice methods to measure RMR .The study was scheduled for a total of eight consecutive days Fig. , and theRunners were instructed to record every meal, including drinks and nutritional supplements, with photographs, and report the meals to Registered Dietitian Nutritionists (K.I.T. and Y.Y.) via daily e-mails, which included details regarding the type of food, ingredients, seasoning, and preparation. These details were obtained from and confirmed by the participants’ parents who served the meals. A ruler supplied by the nutritionists was incorporated into each photo, taken before and after each meal, to estimate the volume of food consumed. As the participants consumed steamed rice with almost every meal, the weight of the rice was measured each time using a digital scale .On the seventh or eighth day of the study, the nutritionists conducted face-to-face interviews with each subject to confirm the accuracy of all records. Daily EI was calculated using the Standard Tables of Food Composition in Japan - 2015 (Seventh Revised Version) . The mea2) of each runner. We used running speed to estimate EEE for the running training, whereas heart rate (HR) was used for resistance training and agility drills. A timekeeper checked and recorded lap times  with a stopwatch for each subject. Similarly, the participants recorded their own lap times with a sports wristwatch and attempted to run at the speed set by the coach. Each lap time was recorded in the training logs, and the running speed was calculated by the lap time for each distance. HR was recorded every 5 s by a wearable HR monitor  and uploaded to the POLAR FLOW website [EEE was calculated for running and other types of training (resistance training and agility drills) separately, using individual prediction equations for the total oxygen consumption (VO website . The HR 2 (ml⋅kg−1⋅min−1) for three or four sets at 10, 12, 14, and 15 km⋅hr−1. The duration of each stage was set at 5 min and separated with more than 5 min rest. The submaximal steady-state VO2 was plotted according to the velocity and HR, and equations to estimate VO2 were determined using linear regression analysis. The mean R2 of the regression lines was 0.986 (0.920−1.000) and 0.992 (0.967−1.000), respectively.The runners were assessed on a treadmill at 1 % slope with breath-by-breath indirect calorimetry  to yield submaximal steady-state VO−1 of O2 and subtracting RMR  of the equivalent duration of exercise. The mean EEE for all seven days was analyzed.The participants reported that they had occasionally engaged in sports activities, such as volleyball or swimming, apart from those in their regular training program. Although the amount of energy expenditure in these activities was relatively minor compared to regular training, we included them in calculating total EEE, using a youth compendium of physical activities . FinallyDaily EA was calculated by subtracting EEE from EI and adjusting for fat free mass (FFM). The means of the seven days were calculated and used for analysis. As the EI on day 1 for one subject, and on days 1 and 2 for another subject, were not available, we calculated these means for six and five days, respectively, for EA as well as EI and EEE.−1 FFM⋅d−1 was defined as low EA according to the American College of Sports Medicine [−1 FFM⋅d−1 to identify optimal EA [EA below the threshold value of 30 kcal⋅kg3. The room had a bed with a thick and comfortable mattress , a neck pillow made of a pressure-relieving material , a TV set, washbasin, and a toilet. The airflow was kept at 50 L⋅min−1 with temperature and relative humidity set to 25.0° C and 50.0 %, respectively. The air was analyzed by mass spectrometry . Calibration was performed periodically. VO2 and carbon dioxide production were calculated according to Henning et al. [RMR was measured using a whole room calorimeter  early in the morning after overnight sleep. The room measured 3.7 (W) × 2.7 (D) × 2.5 (H) m with an internal volume of 25.2 mg et al. , and eneg et al. . The accThe participants were familiarized with the procedure by visiting our laboratory and observing the facility prior to the study to reduce emotional stress. They entered the room after finishing dinner (18:00 − 20:00) the day before RMR measurement  as per their routine, whereupon calm, classical music  was played through a wireless communication device  for 3 min, and the room was dimly lit using indirect lighting. After confirming that the subject was fully awake using the communication device, they were asked to keep calm and stay motionless. If necessary, they could turn over and stretch gently, lying on the bed for a few minutes, or use the toilet, before RMR measurement.For RMR measurement, the participants were instructed not to move on the bed and remain supine for 40 to 60 min (50 ± 12 min). The time was announced every 5 min in a gentle and quiet voice during the measurement using the wireless device. We ensured that the participants remembered every announcement after finishing the RMR measurement and that they remained awake during measurement.−1) for Japanese females (J1): < 18 years old (n = 15), 7.64 × body mass (kg) + 4.22 × height (cm) – 22.5 × age (years) + 526 [n = 3), (0.0481 × body mass (kg) + 0.0234 × height (cm) – 0.0138 × age (years) – 0.9708) × 1000/4.186 [The steady-state of calculated energy expenditure was visually assessed by a PC monitor after obtaining approximately 20 min of data, a duration which was adopted to determine RMR  + 526 ; ≥ 18 ye00/4.186 . Since a00/4.186 , and the00/4.186  to prediTBLH) (g⋅cm−2), with Z-score and body composition, was measured by DXA , early in the morning directly after RMR measurement. A quality assurance test was performed before each scan using a phantom provided by the manufacturer. We assessed test-retest reliability using 10 girl runners from the same team as the participants. The CV for BMD, fat mass, and lean soft tissue mass were 0.4 %, 1.8 %, and 0.3 %, respectively. The same investigator (N.K.) conducted all scans, and enCORE software versions 13 and 16  were used for data processing. Body mass index (BMI) was calculated as body mass (kg) divided by height squared (m2). FFM was calculated by adding bone mineral content to lean soft tissue mass.Height and body mass were measured using an automatic digital scale . Areal bone mineral density (BMD) of total body less head . T-tests were performed to define the differences between two EA groups with Levene’s test for equality of variances. The Fisher’s exact test was used to assess the difference in frequency of amenorrhea between the two groups. Pearson’s correlation analysis was used to evaluate the association between two continuous variates. We primarily tested the hypothesis that RMR reduces linearly with a decrease in EA. Further, the relationship was evaluated for each group of the EA level. A P value < 0.05 was considered statistically significant. Given the exploratory nature and the small number of study participants, effect sizes were reported as Hedges’ g with a correction for small sample bias for t-tests [All statistical analyses were conducted under the guidance of a statistical expert (K.O.) with SPSS t-tests  and ϕ fo−1, respectively. EA varied widely from 6.5−55.4 kcal⋅kg−1 FFM⋅d−1, and six of the 18 participants were categorized into the low EA group. The participants were exclusively thin and lean . Similarly, the low EA group had a higher percentage of body fat, but without significant difference from their counterparts. The running performances in participants with EA above the threshold were better than those with low EA. However, these were not significantly different; the personal best records of 1500 and 3000 m races were 4 min 40 s ± 15 s and 9 min 55 s ± 34 s in participants with EA above the threshold, and 4 min 49 s ± 12 s and 10 min 4 s ± 27 s in those with low EA .The mean daily EI and EEE of the participants ranged from 1236 to 3016 and 441 to 1285 kcal⋅dn = 9) were amenorrheic; however, there was no significant difference in the frequencies of amenorrhea between those two groups . EA was larger in participants without amenorrhea than in those with amenorrhea; however, it was not statistically significant .Half of the participants  was significantly higher in participants with optimal EA than in those with non-optimal EA . Measured RMRs were lower than predicted RMRs, regardless of EA level, and there were no significant differences in RMR ratios between the participants with low EA and those above the threshold, irrespective of the prediction formulae used . However, RMR was not significantly correlated with EEE and EA . The association between RMR and EA appeared to be non-linear .Pearson’s correlation analyses demonstrated that RMR was significantly correlated with EI  of low EA. However, further reduction in RMR was not observed along with continuous lowering of EA. This might suggest that RMR would be robustly sustained in low EA states among competitive athletes who regularly endure strenuous exercise training. Melin et al. [−1 FFM⋅d−1) of the athletes with the lowest EA  was similar to those with optimal EA  (p = 0.06). The analysis was performed by traditional group comparison using the operational cut-off values of EA. However, using a dichotomous or group comparison might lead to confusing results of their relationship, depending on which value is adopted for the analysis. In fact, we used EA = 30 kcal⋅kg−1 FFM⋅d−1 to distinguish low EA from non-low EA, with no significant difference observed in RMR. On the contrary, if we used EA = 45 kcal⋅kg−1 FFM⋅d−1 to differentiate optimal EA from non-optimal EA, RMR would be significantly lower in the non-optimal EA group than in the optimal EA group. This finding is consistent with the results of the study by Melin et al. [We observed that RMR reduced with the decline of EA toward the threshold value  values reported by previous studies of adult female athletes  [RMR is reduced by caloric restriction among sedentary individuals . Such anFFM⋅d−1) , 39. Onc−1) showed large weight loss; however, RMR remained unchanged. Zauner et al. [A paradoxical increase in RMR despite energy deprivation has been reported. Koehler et al.  studied r et al.  reportedr et al. , 47. A rr et al. .Several factors can be considered for the disproportionally high RMR in participants with low EA. First, EA includes energy expenditure relevant to non-exercise activity and diet-induced thermogenesis, and larger decreases in these components may occur in participants with low EA to avert further suppression of RMR. Second, thermogenic responses by adrenaline infusion were not reduced in underfed conditions . This maTo the best of our knowledge, this is the first research demonstrating that RMR would be sustained even in low EA states among competitive teenage girl runners. A major strength of this research is the use of a rigorous method to evaluate resting energy expenditure. A change of approximately 10 % could occur in measured RMR according to the condition of the participants . The errAnother scientific merit of this study is that our research provides additional data on Asian athletes to the field of research on EA. This investigation will similarly provide new insight on low EA concerning resting energy metabolism. The non-linear relationship between EA and RMR draws attention to the use of a reduced RMR as a surrogate marker for low EA. Finally, the results were obtained from free-living athletes. We could conduct the measurements without an adverse effect on the daily routines of training and student life. Clinically, this would help generalize the results to athletes in real life.2 during training sessions, in free-living athletes. We used parent reports [Several limitations of the present study should be addressed. First, to seek homogeneity of participants and use a whole room calorimeter, we could not substantially increase the number of participants. Due to the small number of participants, the correlation analysis results between EA and RMR should be carefully interpreted. However, we would like to highlight runners with relatively high RMR despite extremely low EA, rather than determine the statistical significance by testing a null hypothesis, which can be determined by larger sample sizes. Second, a cross-sectional design was used for the study, and changes in body mass, body composition, or the long-term history of energy balance in the runners were not investigated. Hence, longitudinal observation is necessary to elucidate the chronic effect of low EA on RMR. Besides, we were not able to describe if our results were reflected by race- or age-specific effects. The low EA threshold  was base reports  and food reports  to confi reports . This woThis study showed that low EA is commonly observed among highly competitive and lean Asian girl runners, as reported in Caucasian adult female athletes. Some of them had extremely low RMR. However, the study results suggest that the RMR did not change with a decrease in EA among these girl runners, particularly when the EA of the runners was below the threshold of low EA. Furthermore, the degree of RMR suppression compared to the predicted value may not appropriately reflect the EA level. These findings might be related to race- or age-specific effects or protective effects of resistance training on RMR. Although further studies with experimentally induced low EA are necessary to confirm the findings, the identification of free-living teenage girl runners with low EA using RMR as a proxy for EA change should be performed cautiously, considering the above findings.


With the evolving knowledge on hearing as a potentially modifiable mid-life risk factor for dementia, identification of people at risk becomes increasingly important. People with mild cognitive impairment (MCI) presenting to specialist memory services represent a key “at-risk” target population for audiological evaluation, but few services have established this pathway. This study sought to examine the patient experience and understanding of this process.All patients with MCI attending a tertiary referral memory service referred for audiology review were contacted. A patient survey was delivered over the phone. Outpatient letters and the memory clinic database were reviewed.Twenty patients with MCI were included in the survey. Eight  had self-reported hearing loss. Upon formal audiological assessment seventeen  had objective evidence of hearing loss; nine  with mild-moderate and eight  with moderate-severe hearing loss. Only six patients  recalled having the rationale behind having a hearing test as part of their memory work-up explained to them. However, the majority  felt a hearing test was an important part of their memory assessment. Just seven patients overall  identified a link between hearing-loss and cognition. All patients who provided feedback on the service itself made positive comments, although  felt they did not get adequate information about the results.A significant proportion of people with MCI had de-novo evidence of hearing impairment upon assessment. Patients are satisfied with incorporating audiological evaluation into a memory clinic assessment, however clear communication around indication, recommendations, and follow-up ensuring compliance is required.The online version contains supplementary material available at 10.1186/s12877-021-02701-0. Much recent research has been focused on interventions to identify and modify the risk factors for dementia, particularly since the publication of the Lancet meta-analysis in 2017 , making Both self-reported and informant reports of hearing impairment are associated with cognitive decline , 5. In pHearing impairment can also be associated with under-performance on cognitive testing, one of the hypotheses for its association with cognitive impairment . Many ofA number of interventions for hearing loss exist, from auditory rehabilitation and listening devices to hearing aids and cochlear implants . It is lWith relatively low cost and safe options available, screening for hearing impairment is an attractive option for patients with MCI. To our knowledge, just one study to date examines patients’ perception of this type of referral pathway. Wolski et al.  describeThis study sought to explore the patient experience, tolerability and understanding of having an audiology assessment as part of the process of their memory clinic assessment in a group of patients with MCI, and the challenges associated with this pathway. As more research and knowledge around hearing impairment and its links to dementia become available, it will become increasingly relevant how patients feel about audiology testing and intervention.This study was carried out in a tertiary referral memory service. This clinic offers a multi-disciplinary approach to cognitive assessment, diagnostics and post-diagnostic support. All patients diagnosed with MCI are offered routine audiology referral since 2018, with the referral made on the basis of a cognitive diagnosis, rather than subjective hearing loss. These patients then attend a separate specialist assessment in the audiology department, lasting approximately 90 min. This involves a full audiological history, otoscope, tympanometry, pure tone audiometry, speech audiometry, with hearing test and Ear Nose and Throat (ENT) referrals made as required.This study included all patients with MCI who agreed to referral for audiology assessment from the memory service. MCI diagnosis was made by expert consensus discussion, following review of extensive cognitive testing, clinical history and examination, collateral history and neuroimaging, and using the National Institute on Aging diagnostic criteria .A patient survey was constructed, based on previous similar studies and aiming to provide a mix of open and closed ended questions to yield both qualitative and quantitative data. The survey used was developed specifically for the purposes of this study  years and just under half (45%) were female. Further demographic information, past medical history, risk factors and cognitive assessment scores are summarised in Table Medical co-morbidities were common, particularly cardiovascular risk factors. Of the twenty patients included, eighteen  had at least one of: hypertension, smoking history, type 2 diabetes or history of cardiovascular or cerebrovascular disease. Eleven patients  had at least two of these risk factors. Polypharmacy was also prevalent, with a mean and median of 5 regular medications per patient. The mean Mini Mental State Examination (MMSE) score was 26.4 (SD = 2.3).2  = 2.81, p = 0.094. Just six patients  met the speech discrimination score of 100% in at least one ear, a marker of functional hearing ability. The mean MMSE for patients with moderate to severe hearing loss was 25.8, versus 27 for those with normal or mild to moderate hearing loss (p = 0.12), showing a tendency towards better results on cognitive assessment for the group with better hearing.On audiology assessment, seventeen respondents 17/20, 85%) had at least a mild hearing loss detected. Categories of hearing loss are summarized in Fig. 0, 85% haThe first part of the patient survey looked at self-reported hearing issues, and assessments and interventions for hearing prior to their memory clinic assessment Table . Within Eleven patients  had hearing deficits sufficient to necessitate use of a hearing aid following their audiology assessment, with eight  referred for a hearing aid, and a further three patients who were offered referrals, but declined due to financial constraints.Only five patients of those recommended for a hearing aid , had one available for use at the time of the survey, and of those, one never wore it, citing discomfort. An average of 11.2 (range 2–17) months had passed between their audiology assessment and the survey being carried out. Only one patient wore their hearing aid regularly, one occasionally and two in particular situations, specifically when watching TV and when leaving their home. One patient reported a subjective positive impact on their memory from wearing a hearing aid, with two reporting a positive impact on their participation in hobbies and past-times and one reporting a positive impact on their social life and relationships. Of note, none of those who wore their hearing aids reported any negative impact as a result of doing so. When patients were asked about their overall experience, the majority of responses were positive. The main themes identified related to the amount of information or results received, and to the process itself. With regard to the information or results received, ten patients  made positive comments about the amount of information, results and recommendations—“I got plenty of information” and “Things were explained well” were some of the positive comments in this area. However, not recalling whether information was given or whether it was adequate, was another recurring theme. This is illustrated by comments made by two patients; “I’m not sure if I got any information on the results, maybe I was told on the day” and “I think I got enough information, that I can remember”. A further two felt that the amount of information given was inadequate; “I don’t remember getting the results” and “I got very little information, they could have given me more”.Twelve patients made comments on the process itself, all of which were positive. One theme in this area was the sentiment that it was an important part of their overall care or one that they felt fortunate to have had the opportunity to engage with, illustrated by comments such as “I’m happy to have had the hearing test” and “I’m lucky to be looked after”. Other comments in this area were on the logistics and domains assessed during the audiology assessment, with comments such as: “It was a very extensive evaluation” and “more thorough than I expected”.Of the thirty patients with MCI contacted at the beginning of the study, nine 30%) had forgotten having had an audiological evaluation at all, a relevant group in the context of examining the patient experience. The comparison between this group and those who could recall their audiology assessment is summarised in Table 0% had foPatients with MCI attending the memory clinic in this tertiary referral centre who agreed to audiology assessment were satisfied with their experience of having an audiological evaluation, and rated it as an important part of their memory assessment. With the evolution of the link between hearing loss and memory disorders, establishing that this pathway is acceptable to patients is important, and may lead to development of a framework for integration of audiology assessment into the practices of memory clinics. Further studies may focus on those who declined audiology assessment and their perception of this pathway.Audiology assessment and intervention for hearing loss are clearly important in populations with cognitive disorders. Hearing loss has been established as a major mid-life risk factor for dementia  and is aPatient recall of the information provided around audiology assessments was poor, with 30% of patients contacted unable to recall having had an audiology assessment. Significant numbers also stated that the rationale behind having a hearing test as part of their memory clinic assessment was not explained to them. Furthermore, the minority of patients surveyed identified a link between hearing loss and memory disorders. There was no significant correlation between self-reported hearing loss and objective hearing deficits, in keeping with previous studies  and undeThe group of patients included in this study are a somewhat vulnerable cohort, with high levels of medical co-morbidity and polypharmacy. The majority of patients had more than one significant cardiovascular comorbidity, reflecting the high population prevalence of these conditions . Risk faThis was a small-scale study in a single centre. Although all patients with MCI who agreed to audiology referral were included, this potentially omits patients who declined assessment as hearing was not a significant issue for them. Recall bias is evident, with a higher number of patients acknowledging subjective hearing loss at the time of the survey than did at the time of audiology assessment. For different patients, different time periods had elapsed between when the survey was administered and when their audiology assessment had been carried out, potentially excluding patients who may have been able to recall having had an audiology assessment at an earlier date. The range of time elapsed prior to the survey may also have impacted on the accuracy of answers to certain questions and opinions expressed. Data on educational attainment, as well as basic and instrumental activities of daily living was not available for all participants.Patients who participate in routine audiological evaluation as part of a memory clinic assessment are satisfied with this pathway. The amount of hearing loss detected highlights the importance of incorporating some kind of audiology screening into memory clinic pathways, especially given the impact that hearing loss can have on a patient’s risk of future cognitive decline, functional status and quality of life. Without such a pathway, hearing loss can frequently be overlooked and the opportunity to modify a patient’s dementia risk factor profile can be lost as a result. This needs be done in tandem with excellent communication and education about the links between hearing impairment and memory disorders, as well as a pathway whereby patients can easily access interventions.Additional file 1: (DOCX 17 kb)


Johanson-Blizzard syndrome (JBS) is a rare autosomal recessive hereditary disorder characterized by multi-system involvement and facial dysmorphic features. One of the most common symptoms in JBS patients is bilateral severe to profound sensorineural hearing loss. The objective of this report is to highlight the performance of those patients after receiving cochlear implants (CI) as a management for their hearing loss. In this study, we reviewed the medical records of one female child diagnosed with JBS before and after cochlear implantation, with a particular focus on their auditory and language performance. After receiving the cochlear implant, our patient showed substantial improvement in her hearing threshold and communication abilities when compared to the preoperative condition. In conclusion, although cochlear implantation is considered a good approach for the management of JBS patients, the development of spoken language is not always achieved. Johanson-Blizzard syndrome (JBS) OMIM: #243800) is a rare autosomal recessive disorder first described in 1971 by Johanson and Blizzard 43800 is .To our knowledge, only two studies reported the outcomes of cochlear implantation with JBS patients, however one of them was in Russian ,7. The oA seven-year-old female with JBS presented to our clinic for evaluation of the possibility of cochlear implantation for bilateral SNHL. She was born in the USA to healthy first-cousin parents with no family history of any major or genetic disorders. She was found to have facial dysmorphic features such as hypertelorism, a beaked nose, pinpoint chin, low hairline, wide spaced small nipples, and café au lait spots distributed over her body. She was diagnosed with multiple conditions known to be associated with JBS such as pancreatic insufficiency, patent ductus arteriosus with left to right shunt, recto-vestibular fistula, tethered cord, and global developmental delay.Our patient failed the newborn hearing screening test bilaterally. At the age of three months, her hearing evaluation using auditory brainstem response revealed bilateral severe to profound SNHL. At the age of five months, she was fitted with bilateral hearing aids. After one year of follow up, her parents reported limited aided responses. They also reported that she was not reacting except to loud sounds along with speech delay. Moreover, her mode of communication was mainly by pointing and responding to simple commands, and that she has normal playing skills. At the age of three years, she was referred to the cochlear implantation (CI) committee in our hospital for evaluation. Radiological evaluations revealed right cochlear anomaly with incomplete partition type II of the right middle and apical cochlear turns with enlarged vestibule, absent modiolus, and hypoplastic cochlear nerve Figure . It alsoAt four years of age, she received a left CI  with complete insertion of the electrode array. Intra-operative objective assessment revealed normal impedances and presence of electric compound action potential (ECAP) responses from all electrodes. There were no recorded postoperative complications. Following the implantation, the patient was regularly brought to her follow-up appointments and rehabilitation clinic. She showed improvement with the rehabilitation process. Her most recent speech detection threshold (SDT) was 35 decibel (dB) hearing loss (HL) and the aided hearing threshold ranged between 35 and 40 dB HL Table . After tJBS is a rare autosomal recessive condition caused by mutations in the gene encoding UBR1. Our patient presented with multi-system involvement, delayed global development, and average intellectual disability. Our findings are consistent with other studies which reported a very similar picture of JBS . HoweverOne of the main problems in our case was the severe to profound SNHL which negatively impacted her communication abilities. Unfortunately, our patient did not benefit from hearing aids which made her a good candidate for CI. The results of radiological evaluation revealed congenital anomaly of the right cochlea and normal left inner ear. Hence, unilateral left ear implantation was conducted for this patient. Our patient showed substantial improvement in her hearing threshold and communication abilities when compared to the preoperative condition Table . These rIn general, early diagnosis of JBS syndrome can improve patient outcomes through guiding variable treatment interventions. Early audiological evaluation is recommended for those patients to diagnose any hearing impairment as early as possible, to maximize the good outcome of the cochlear implantation. In our opinion, early and bilateral CI is highly recommended as management of SNHL of JBS. Additionally, prenatal genetic counseling is critical, particularly in cases of consanguineous marriage.Our findings indicate that, while cochlear implantation is a viable option for managing JBS patients with bilateral SNHL, other factors such as the patient's intellectual disability and other systems affection can significantly affect postoperative outcomes, as spoken language development is not always achieved. The current data support the use of early CI in JBS patients. Multidisciplinary care, some educational services for hearing impairment, and specialist counseling tactics for behavioral manifestations following CI may all contribute to improving the quality of life for JBS patients.