To characterize the contributions of the loss of energy-expending tissues and metabolic adaptations to the reduction in resting metabolic rate (RMR) following weight loss.Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy study. Changes in RMR, body composition, and metabolic hormones were examined over 12 months of calorie restriction in 109 individuals. The contribution of tissue losses to the decline in RMR was determined by weighing changes in the size of energy-expending tissues and organs  assessed by dual-energy X-ray absorptiometry with their tissue-specific metabolic rates. Metabolic adaptations were quantified as the remaining reduction in RMR.A secondary analysis was conducted on data from the p < 0.001). On average, 60% of the total reduction in RMR were explained by energy-expending tissues losses, while 40% were attributed to metabolic adaptations. The loss of skeletal muscle mass (1.0 ± 0.7 kg) was not significantly related to RMR changes , whereas adipose tissue losses (7.2 ± 3.0 kg) were positively associated with the reduction in RMR  and metabolic adaptations . Metabolic adaptations were correlated with declines in leptin , triiodothyronine , and insulin .RMR was reduced by 101 ± 12 kcal/d as participants lost 7.3 ± 0.2 kg (both During weight loss, tissue loss and metabolic adaptations both contribute to the reduction in RMR, albeit variably. Contrary to popularly belief, it is not skeletal muscle, but rather adipose tissue losses that seem to drive RMR reductions following weight loss. Future research should target personalized strategies addressing the predominant cause of RMR reduction for weight maintenance. Worldwide obesity has tripled in the last decades, with more than 1.9 billion and 650 million adults considered overweight and obese, respectively , 3, weigAlthough reductions secondary to weight loss have been reported for most components of TDEE , reductiIt has been traditionally assumed that RMR preservation is enhanced when fat-free mass (FFM) is maintained during weight loss as FFM is considered the primary determinant of RMR . FurtherYet, even when the contributions of organs and tissues are accounted for, RMR continues to decline beyond what would be expected based on the loss of energy-expending tissues. Müller et al. reported that only about one-third of the RMR reduction following 3 weeks of calorie-restricted weight loss was accounted for by metabolically active tissue, leaving two-thirds of RMR changes unexplained . This unWhile both of these distinct phenomena—the loss of energy-expending tissues and the reduction in the metabolic activity of the remaining tissues—contribute to RMR reduction, it is unclear whether each contributor occurs independently or whether the magnitude of different tissue losses impacts the extent of RMR reductions and metabolic adaptations. The purpose of the present analysis was to quantify the unique contribution of these two components to RMR reduction during prolonged weight loss in healthy normal weight and overweight individuals and their relationship with each other. To address this objective, we retrospectively analyzed data from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) , a largeThe present investigation is a secondary analysis of data from CALERIE , a randoData were obtained via download of the publicly available dataset . Data fr2 were randomly assigned 2:1 to 25% caloric restriction (n = 145) or control group (n = 75). For the purpose of our analysis, participants in the non-restricted control groups were excluded as only minimal weight loss was expected. Further, data from participants without complete baseline or 12-month measurements were excluded.Potential participants were screened for previous eating disorders, significant health problems, recent substantial weight loss and/or participation in CALERIE Phase 1, and use of medication except oral contraceptives. Following initial inclusion, 220 male and female participants 20–50 years of age with a body mass index (BMI) from 22 to 27.9 kg/mData used for the present analysis included assessments of body weight, body composition, RMR, and metabolic hormone concentrations. Body weight was assessed every 3 months during a clinical visit using an electric scale . Body composition was measured using dual-energy x-ray absorptiometry (DXA) via a standardized protocol using a 4500 A, Delphi W, or Discovery A scanner  at baseline and months 6 and 12. RMR was measured using indirect calorimetry  at baseline and months 6 and 12. Metabolic hormones, including insulin, leptin, triiodothyronine (T3), and insulin-like growth factor 1 (IGF-1), were assessed from venous blood samples at baseline and month 12.The extent of changes in RMR attributable to the losses of energy-expending tissues and organs was calculated based on the contribution of the primary organs and tissues contributing to whole-body RMR , 32. OrgT-tests using the Holm–Bonferroni method.Statistical analyses were performed with R . If not labeled otherwise, all data are presented as mean ± standard error of the mean. Changes in outcomes between baseline and months 6 and 12 were assessed using pairwise, paired To determine how reductions in RMR and metabolic adaptations were related to skeletal muscle and adipose tissue losses, linear regression analyses were conducted between outcomes and changes in measured RMR, changes in RMR due to tissue losses, and metabolic adaptations. Associations between metabolic adaptations and measured RMR with changes in adipose tissue and skeletal muscle mass were further assessed using Pearson’s correlation coefficient.To visualize differences between individuals who lost the most and least of the specific tissues, participants were grouped into quartiles based on their individual changes in skeletal muscle and adipose tissue, respectively, with the lowest (Q1) and highest (Q4) quartiles referring to the participants with the greatest losses and the smallest losses and/or gains in a specific tissue, respectively. Differences in RMR and metabolic adaptations between quartiles were assessed using generalized linear model analyses adjusted for confounders , using Q1 as reference quartiles.p < 0.05).The association between metabolic adaptations and hormonal changes was assessed using Pearson’s correlation coefficient. Statistical significance was considered with a probability of error <5% (n = 109) with complete data at baseline and 12 months  from baseline to 6 months and declined by an additional 0.7 ± 0.2 kg (p < 0.001) from 6 to 12 months, resulting in a total weight loss of 8.0 ± 0.3 kg (p < 0.001)  with no further losses from 6 to 12 months  and further from 6 to 12 months (p < 0.001) for a total loss of 7.2 ± 3.0 kg. No or only minimal changes were observed for brain, inner organ, bone and residual mass (Table Body weight declined by 7.3 ± 0.2 kg p < 0.00 from basp < 0.001) from baseline to 6 months, and there was no further decline from 6 to 12 months  from baseline to 6 months, with no further decline from 6 to 12 months (p = 0.58). Per our operational definition, the additional 40 ± 11 kcal/d reduction in measured RMR were attributed to metabolic adaptations.At baseline, there was no difference between measured and predicted RMR . Measured RMR decreased by 101 ± 12 kcal/d  nor between changes in skeletal muscle mass and metabolic adaptations (p = 0.36)  and between changes in adipose tissue mass and metabolic adaptations  . As a result, the proportion of metabolic adaptations accounting for the overall reduction in RMR increased steadily from Q1 (5.6%) to Q4 of skeletal muscle (63.9%), although this increase failed to achieve statistical significance (p = 0.11).Upon examination of the relationship between tissue losses and the reductions in RMR and metabolic adaptations, there were no discernible associations between changes in skeletal muscle mass and measured RMR p = 0.6 nor betns p = 0.6 .When dividing participants into quartiles based on adipose tissue losses, the reduction in measured RMR declined as less adipose tissue was lost, as did the reduction in predicted RMR from tissue losses Fig. . In indip < 0.001). T3 (−14.3 ± 2.0%) and insulin (−14.3 ± 4.6%) were also significantly reduced (both p < 0.001). Reductions in leptin , T3 , and insulin  were all significantly correlated with metabolic adaptations . T3 −1.3 ± 2.0%The present retrospective analysis of data from a large, well-controlled randomized trial confirms that RMR is reduced by a magnitude of ~100 kcal (~7%) in response to weight loss of ~11% achieved through caloric restriction in healthy normal weight and overweight individuals. On average, only 60% of the total reduction in RMR were explained by losses of energy-expending tissues, while the remaining 40% of RMR reduction can be attributed to metabolic adaptations. However, there was substantial variability between participants in RMR changes as well as in the contributions of tissue losses and metabolic adaptations to RMR changes.The observed RMR reduction by 7% is similar to previous, albeit shorter and more aggressive weight loss studies, such as in individuals who lost 9.6 kg  and exhibited a 9% reduction in RMR  after 8 Upon analysis of tissue-specific weight loss in CALERIE, we observed that the primary components lost during the intervention were skeletal muscle and adipose tissue, while the remaining organs and tissues were largely preserved. The selective loss of these two components aligns with a previous examination of the specific composition of FFM loss during weight loss, which observed no disproportionate loss of high-metabolically active organs when compared to skeletal muscle . While bOur results differ from other studies reporting that reductions in RMR were almost entirely explained by reductions in FFM, such as the 6% reduction in RMR following 3 weeks of a low-energy diet and 1.9 kg reduction in FFM  or the eWhile tissue changes explained slightly more than half of the RMR reduction following weight loss (60%), Fig. Our analysis further indicated that the extent of metabolic adaptations in the present study was strongly related to the amount of adipose tissue lost. This positive association between adipose loss and metabolic adaptations is in agreement with previous studies in individuals with obesity undergoing gastric bypass surgery or an intensive weight loss program . Both sep = 0.27).Despite multiple literature reports of metabolic adaptations following weight loss, it is important to note that there is no gold standard method for its direct measurement. Metabolic adaptations represent the difference between measured and predicted RMR. To optimize its quantification, we utilized DXA data, which enabled more specific quantification of energy-expending tissues and organs to improve the prediction of RMR . The equWhile the present analysis describes the contribution of changes in energy-expending tissues and organs and metabolic adaptations to the reduction in RMR in a large caloric restriction trial, it was conducted in non-obese individuals, whose weight loss requirements are not the same as individuals with obesity. However, given that changes in non-adipose tissues tend to be greater in leaner individuals , the nonOur analysis demonstrates that RMR is inevitably reduced after weight loss in healthy normal weight and overweight individuals and that this reduction occurs through a combination of the loss of energy-expending tissues and metabolic adaptations. As hypothesized, the loss of energy-expending tissues—predominantly skeletal muscle and adipose tissue—contributed to the reduction in RMR, although on average for only ~60% , leaving the remaining 40% of the RMR reduction  attributable to metabolic adaptations. More importantly, the contribution of tissue losses and metabolic adaptations to overall RMR reduction was highly variable between individuals. Contrary to common belief, there was no discernible relationship between the loss of skeletal muscle, the primary lean tissue component that is lost during weight loss, and reductions in RMR. Conversely, the loss of adipose tissue was related to reductions in RMR and metabolic adaptations, whereby metabolic adaptations were greatest in individuals who lost the most adipose tissue. Given the differential impact of these components to RMR reduction following weight loss, future research should examine whether the preservation of the tissues or their metabolic activity yields differential results toward RMR reductions and weight maintenance and whether more personalized strategies addressing the specific cause of the RMR reduction may help maximize weight loss and prevent weight regain.Supplementary Figure and Table LegendsSupplementary Table 1Supplementary Figure 1Supplementary Figure 2


The objective of this study was to investigate current perception and expected price of personal sound amplification products (PSAPs) and to analyze influencing factors through multi-center hospital-based surveys of outpatients, caregivers, and hearing experts.A multi-center exploratory cross-sectional study was conducted in two groups of respondents with two separate surveys: 1) a perception survey of patients and caregivers who visited an otorhinolaryngology outpatient clinic in 5 general hospitals and 2) an opinion survey of hearing specialists about the expected price of PSAPs. A total of 197 outpatient visitors responded to the perception survey, and 42 hearing specialists responded to the opinion survey.P = 0.002), and the individuals with greater severity of subjective hearing loss showed significantly higher perception of PSAPs (P = 0.002). The expected price of PSAPs of the outpatient visitors was 933.9 USD  per ear. Mean expected price of PSAPs of hearing specialists was 291.3 USD  per ear.Overall perception score (18 questions) was 3.04 . When 5 categories of perception  were analyzed, cost and expectation showed the highest scores of 3.33  and 3.33 , respectively, and needs showed the lowest score of 2.23 . The ≥ 60-year-old group showed significantly higher perception of PSAPs (The perception rate of PSAPs was very low, and there was a discrepancy in the expected price of PSAPs between patients/caregivers and hearing experts. Hearing specialists should make effort to improve perception of PSAPs. Medical, economic and social development has led to worldwide population ageing, and it has been especially fast in Eastern and South-Eastern Asia. United Nations reported in 2019 that the number of persons aged 65 years or over was 703 million globally and 260 million in Eastern and South-Eastern Asia . HearingThere are several barriers to adopting HAs, including cost, social stigma, low motivation, and limited access to health care providers , 11. To When compared to HAs, PSAPs lower the barrier on accessibility with their cheaper price and no requirement for consultation. The cost barrier is lower for PSAPs (approximately $20–400) than for traditional HAs . In addition, while professional consultation is required for traditional HAs, it is not needed for PSAPs . Recent Direct-to-consumer hearing devices such as PSAPs are leading changes in the hearing aid market . Unlike Thus, in this hospital-based, multi-center, cross-sectional survey study, we investigated the current perception of PSAPs in five aspects of knowledge, needs, cost, expectation and information, and analyzed influencing factors among outpatient visitors. We also conducted an opinion survey of hearing experts to investigate the perceptions of PSAPs among hospital visitors and the professionals they meet.This study was designed as a multi-center, cross-sectional survey study consisting of two groups of respondents. First, a perception survey was conducted on outpatient visitors. Outpatient visitors consist of any patient or caregiver who visited an otorhinolaryngology outpatient clinic in 5 general hospitals. Participants who had been informed of and agreed to participate in this study filled out a questionnaire under the guidance of a Clinical research coordinator (CRC), who is a nurse trained for this purpose. Second, an opinion survey about the expected price of PSAPs was conducted among hearing specialists by e-mail .A total of 197 outpatient visitors who responded the perception survey to more than 50% (10 questions) were included, and 42 hearing specialists who responded to the opinion survey were included.There is no standardized questionnaire to assess perception of HAs, so the survey by Park et al. was modified for use in this study . The queThe questionnaire included three components: 1) socio-demographic characteristics including age, gender, residence, educational background, economic status, and occupation; 2) clinical characteristics including subjective hearing loss, presence of tinnitus, previous experience with assistive devices by the respondent or his/her family members, respondent willingness to use assistive devices, and expected cost of the PSAPs; and 3) perception status. In the clinical characteristics section, the respondents with hearing loss or tinnitus were asked to evaluate the severity of their symptoms using a visual analogue scale (VAS). In the perception status section, the respondents were asked to respond to 18 questions in five categories on a scale from 1 (strongly disagree) to 5 (strongly agree). The questions were grouped into five categories with similar objectives, which were reviewed by the hearing specialists. Questions 1–4, which were grouped in the knowledge category, evaluated whether the respondents were aware of PSAPs as hearing rehabilitation options and the differences between PSAPs and conventional HAs. Questions 5–6 were grouped in the needs category because they were designed to assess whether the respondents thought assistive hearing devices (AHDs) were necessary for individuals with subjective hearing loss. Questions 7–8, which evaluated the influence of price on decision to purchase, were grouped in the cost category. Questions 9–13 evaluated the respondents’ expectations for the PSAPs and were grouped in the expectation category. Questions 14–18 were grouped in the information category because they were designed to assess whether participants had accurate directions for use of PSAPs. To minimize any bias that could arise from answering the questionnaire, misconception questions were included and were scored in reversal. The opinion survey for hearing specialists contained questions asking the expected price of PSAPs. The questionnaire was written in the Korean language, and translated version of the questionnaire is attached in P-values < .05 were considered statistically significant. All statistical analyses were performed using R version 3.6.0.Categorical variables were age, gender, education background, and economic status data. Reference variables were 20–39 years for age, male for gender, middle school graduate for educational background, and very high level for economic status. Continuous variables were VAS score of hearing loss and VAS score of tinnitus. Robust linear models with perception level and expected annual subscription rate as the response variables were applied. Robust variance estimation was used for standard errors and confidence intervals. In robust models, age, gender, educational background, economic status, VAS score of hearing loss, and VAS score of tinnitus were used as explanatory variables. Bonferroni-corrected This study was carried out in accordance with the Declaration of Helsinki on biomedical research for human subjects, and the study protocol was approved by the institutional review board of each participating hospital .A total of 201 outpatient visitors agreed to participate in the study. Four participants who did not respond to more than 50% (10 questions) of the survey were excluded, and the survey results of 197 respondents were used for analysis. Clinical characteristics of the study population are described in Forty-two hearing specialists responded to the opinion survey, including 29 otologists (69.0%) and 13 audiologists (31%). Mean duration of audiologic occupation was 11.83 years . Seventeen specialists had a Bachelor’s degree (40.5%), 14 specialists had a Master’s degree (33.3%), and 11 specialists had a Doctoral degree (26.2%).Among the 197 outpatient visitors who responded to more than 50% of the survey questions, 50 (25.4%) had considered using AHDs, and 23 (11.7%) recognized the difference between PSAPs and HAs. Five respondents (2.5%) had used PSAPs, and only 2 respondents (1.0%) were using a PSAP at the moment. Among the 192 respondents who had never used PSAPs, 21 (10.94%) replied that they would consider using PSAPs in the future.Of 197 respondents, 115 respondents had subjective hearing loss. Of 115 respondents with subjective hearing loss, 48 (41.7%) had considered assistive hearing devices, 14 (12.2%) recognized the difference between PSAPs and HAs, and 4 (3.5%) had experienced PSAPs. 111 respondents had subjective hearing loss, but had no experience in PSAPs; of these respondents, 15 (13.5%) responded that they would consider using PSAPs in the future.Overall perception score of 18 questions was 3.04 . When analyzed in 5 categories, cost and expectation categories showed the highest scores of 3.33  and 3.33 , respectively, and the needs category showed the lowest score of 2.23  .P = 0.028); of 5 categories, cost (P = 0.020) and information (P = 0.020) categories showed a significantly higher scores than the 20-39-year-old group . No statistically significant difference in perception of PSAPs was found between the 20-39-year-old group and the 40-59-year-old group. The ≥ 60-year-old group showed statistically significantly higher value on the total perception scores on PSAPs, when compared to the 20-39-year-old group (ld group . No signP < 0.001). Individuals with subjective hearing loss did not show significant difference in total score when compared to the individuals without subjective hearing loss. However, individuals with higher VAS score for hearing loss showed statistically significantly higher value on total score than those with lower VAS score for hearing loss  and very low group (P = 0.020) showed significantly lower expected price of PSAPs when compared to very high group. The respondents with subjective hearing loss showed significantly higher expected price of PSAPs than the respondents without subjective hearing loss (P = 0.048). Other factors such as gender, level of education, and tinnitus VAS scores did not show significant difference in expected price of PSAPs  per ear. The expected price of PSAPs showed significant difference by age group. The expected price by self-estimated economic status was statistically significantly different in low and very low group; low , 745.5 USD  in 40-59-year-old group, and 1014.2 USD  in the ≥ 60-year-old group. Individuals in the 20-39-year old group showed statistically significantly higher willingness to pay higher prices compared to the 40-59-year old group (P = 0.026) .P = 0.033) and in the very low group  showed statistically significantly lower value on mean expected price, when compared to the very high group . In other words, low and very low groups showed lower willingness to pay than the very high group  per ear; mean expected price of premium PSAPs was 487.6 USD , and that of entry PSAPs was 224.9 USD  . In addiIn this study, overall perception of PSAPs was investigated in 197 outpatient visitors who visited an otorhinolaryngology outpatient clinic in five general hospitals. Of 197 outpatient visitors, only 23 (11.7%) had information about PSAPs, and among 116 individuals with subjective hearing loss, only 14 (12.2%) recognized the difference between PSAPs and HAs. Thus, regardless of presence of hearing loss, overall perception of PSAPs is poor in Republic of Korea. Subjective hearing loss and tinnitus did not show significant correlation to the knowledge category score in the perception survey, indicating that even individuals with hearing difficulty or tinnitus do not have enough information about PSAPs.Among individuals with subjective hearing loss, only 5 (3.5%) had experience with PSAPs. This is much lower than the PSAP adoption rate of 9.6% in individuals with hearing difficulties in the United States . In thisWhen the perception of PSAPs of all respondents was analyzed in 5 categories, the score of the needs category was the lowest, and this could be because the perception survey included both individuals with normal hearing and individuals with subjective hearing loss. However, individuals with subjective hearing loss showed significantly higher score in the needs category than the individuals without subjective hearing loss. In other words, individuals with subjective hearing loss showed greater necessity for AHDs than individuals without subjective hearing loss. MarkeTrak VIII and EuroTrak data reported that hearing loss plays the most important role in HA adoption , 21. AltNo statistically significant correlation was shown between perception score and tinnitus in any category. This result is similar to the MarkeTrak VIII and EuroTrak data, which showed that tinnitus is not an important factor for HA adoption. Thus, hearing loss is more critical than tinnitus in selecting AHDs , 21.The ≥ 60-years-old group showed significantly higher scores on information and cost categories, when compared to the 20-39-year-old group; in other words, the ≥ 60-years-old group has more information on the use of PSAPs and is more greatly influenced by the price on making decision to purchase PSAPs. The 20-39-year-old group showed highest mean expected price of PSAPs. This could be explained by low score on information of the 20-39-year-old group, when compared to the ≥ 60-years-old group; the 20-39-year-old group did not have enough information on PSAPs to accurately predict the price. In addition, those with subjective hearing loss in the 20-39-year-old group (26.3%) could have higher will for hearing rehabilitation because they are young, and this could have led to willingness to pay higher prices for PSAPs.In terms of self-estimated economic status, the low-to-very low group showed statistically significantly lower value on mean expected price than the very high group; the middle and high groups showed no significant difference in mean expected price. Previous studies have reported that cost is not a primary barrier to adoption of AHDs and that other factors such as social stigma, perception of hearing loss, and self-efficacy are equally important , 22. OurIn addition, overall expected price of the outpatient visitors was 933.9 USD  per side, which was much higher than the real market price of 20–400 USD in the United States and 70–630 USD in Republic of Korea . Large dOn the other hand, the expected price from the expert opinion survey was within a range of the real market price. In other words, current price policy of PSAPs is provider-oriented, rather than customer-oriented, and possible consumers of PSAPs are willing to pay more for better performance. Therefore, it is necessary for the hearing specialists to educate the general population, especially those in needs, on the real market price of PSAPs to encourage PSAP adoption.One of the strengths of this study is that this is the first perception survey and analysis focused on PSAPs to our knowledge. MarkeTrak 10 investigated PSAPs in addition to HAs, but there was no scientific analysis on PSAPs . In partOne of the limitations of this study is that we could only use a modified survey questionnaire from a previous study conducted in Republic of Korea due to the lack of an official survey form regarding PSAPs. This previous study was conducted by Park et al., and they used a self-verified questionnaire. The questionnaire from the previous study was used to study HAs, so it was modified with regards to PSAPs . TherefoDue to multi-factorial barriers, the role of conventional HAs still has limitations in reaching individuals with hearing loss , 14, 22.In this study, the perception rate of PSAPs was very poor, and age and subjective hearing loss were closely related to perception. Expected price by hearing experts was similar to the real market price, but the otorhinolaryngology outpatient visitors were willing to pay more. Therefore, hearing specialists need to provide accurate information to improve perception of PSAPs and ultimately encourage the patients in need to adopt PSAPs.S1 Appendix(DOCX)Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.S3 Appendix(XLSX)Click here for additional data file.


The findings may imply a central adaptation process due to chronic unilateral auditory deprivation starting before the critical period of auditory maturation. This notion may partially explain the poor outcome of adult cochlear implantation in longstanding single-sided deafness. The findings may suggest a role for the Weber test as a simple, quick, and economical tool for screening poor cochlear implant candidates, thus potentially supporting the decision-making and counseling of patients with longstanding single-sided deafness.The Weber tuning fork test is a standard otologic examination tool in patients with unilateral hearing loss. Sound should typically lateralize to the contralateral side in unilateral sensorineural hearing loss. The observation that the Weber test does not lateralize in some patients with longstanding unilateral deafness has been previously described but remains poorly understood. In the present study, we conducted a retrospective analysis of the medical records of patients with unilateral profound hearing loss (single-sided deafness or asymmetric hearing loss) for at least ten years. In this patient cohort, childhood-onset unilateral profound hearing loss was significantly associated with the lack of lateralization of the Weber tuning fork test (Fisher’s exact test,  Tuning fork tests have remained a mainstay of otologic examination for over a century. The Weber tuning fork test has been mainly used in patients with unilateral hearing loss to distinguish between sensorineural and conductive hearing loss ,2,3,4. IThe study was approved by the ethics committee of Charité Medical University . The analysis involved the retrospective review of the hospital records and audiograms of adult patients with profound unilateral hearing loss (UHL) of at least ten years’ duration who presented to our outpatient department and/or auditory implant clinic between 2018 and 2021. Pure tone audiograms (PTA) determined the ipsilateral and contralateral hearing status. Profound hearing loss was defined by a pure tone threshold average of 90 dB or higher, as described previously ,8. The pThirteen adult patients met the inclusion criteria. Their age ranged from 26 to 78 years (median 54 ± 16.3 years); seven patients were male, and six were female. All patients were diagnosed with profound unilateral hearing loss (UHL) of at least ten years’ duration. The patients’ epidemiological, clinical, and medical history details are summarized in p = 0.0319). The patients’ age, gender, and duration of UHL did not significantly correlate with the Weber test result in this cohort.All but one patient with childhood-onset UHL (seven of eight patients) reported hearing the tuning fork tone during the Weber test but without lateralization to one side. In contrast, all but one patient with adult-onset UHL (four of five patients) reported lateralization to the contralateral side, and no patients lateralized to the ipsilateral side in this cohort. A contingency analysis showed a significant correlation between the age of onset (adult vs. childhood) and the pattern of lateralization of the Weber test . Other factors such as the ipsilateral residual hearing or the contralateral hearing status were not significantly associated with the Weber test lateralization pattern in this patient cohort.Concerning tinnitus, 5 of 13 patients (38%) reported having tinnitus in the worse hearing ear . No patients with childhood-onset UHL reported having tinnitus, while all patients with adult-onset UHL reported having ipsilesional tinnitus. On a statistical contingency analysis, the absence of tinnitus correlated significantly with the lack of lateralization during the Weber test , resulting in a profound hearing loss on the right side. The patient reported having heard no sounds in the right ear since childhood, even in very noisy environments. The patient also denied having tinnitus. The pure tone audiogram (PTA) detected some measurable hearing in the right ear at very high intensities. The contralateral left ear showed sloping sensorineural hearing loss. The Weber test, performed with a 512 Hz tuning fork, consistently failed to indicate lateralization, as the patient has reported hearing the tone in the middle of the head. The PTA is shown in Patient #3: 76-year-old woman who, at the age of 31, underwent a modified radical mastoidectomy for an invasive middle ear cholesteatoma on the right side. As a result of the cholesteatoma and the surgery, the patient had right-sided profound deafness and facial palsy. No recurrence of her cholesteatoma occurred in the following decades. The patient presented to the outpatient department with mastoid cavity problems. The PTA  at 46 years. The contralateral side showed normal hearing. Ten years later, the Weber tuning fork test does not lateralize, but instead, it is heard in the middle of the head. The hearing loss and tinnitus did not recover. The patient elected not to undergo cochlear implantation. The PTA is shown in Patient #9: 54-year-old man with profound left-sided sensorineural hearing loss of unknown etiology since birth. The PTA showed contralateral normal hearing  side. The patient was referred to the cochlear implantation unit for auditory rehabilitation. The PTA is shown in In the present study, we analyzed the results of the Weber test in a small cohort of patients with single-sided deafness (SSD) and asymmetric hearing loss (AHL). The common features shared among all patients in the present study are the unilaterality and long duration of the profound hearing loss, ranging from ten to over seventy years. Despite the anticipated lateralization of the Weber test in the entire cohort, eight of thirteen patients reported the sound heard equally on both sides .We hypothesize that the longstanding auditory deprivation associated with profound unilateral hearing loss (UHL) could lead to a central adaptation process, contributing to the loss of lateralization of the Weber tuning fork test. This observation appears to apply to both SSD and AHL. It is tempting to speculate that the loss of Weber test lateralization could be attributed to central habituation. Observations from daily otologic practice support such a notion. For instance, patients who underwent successful stapedotomies commonly describe environmental sounds as uncomfortably loud for a short period immediately after the surgery . This obThe effects of unilateral auditory deprivation on the auditory cortex have been previously studied ,15. ChilSSD patients should be counseled about the alternatives to cochlear implantation, including contralateral routing of signals (CROS) or bone conduction devices. While those devices may abolish the head shadow effect, they do not restore binaural hearing ,24. In tThe lack of reliable electrophysiologic or radiological outcome predictors for cochlear implantation in SSD patients may reflect the incomplete understanding of the neurobiological changes associated with SSD. Indeed, the outcome of cochlear implantation in SSD is variable and depends on several factors, most notably the duration of deafness ,29,30,31In clinical and experimental studies, the association between tinnitus and SSD has been well established . ChronicIn patients with longstanding SSD referred for cochlear implantation, the poor postimplantation auditory performance can be partially explained by peripheral factors . However, a central habituation component is also likely involved, as shown by electrophysiological and brain mapping studies ,17,40. I


Individuals with CDD suffer infantile onset, drug-resistant seizures, severe neurodevelopmental impairment and profound lifelong disability. The CDKL5 protein is a kinase that regulates key phosphorylation events vital to the development of the complex neuronal network of the brain. Pathogenic variants identified in patients may either result in loss of CDKL5 catalytic activity or are hypomorphic leading to partial loss of function. Whilst the progressive nature of CDD provides an excellent opportunity for disease intervention, we cannot develop effective therapeutics without in-depth knowledge of CDKL5 function in human neurons. In this mini review, we summarize new findings on the function of CDKL5. These include CDKL5 phosphorylation targets and the consequence of disruptions on signaling pathways in the human brain. This new knowledge of CDKL5 biology may be leveraged to advance targeted drug discovery and rapid development of treatments for CDD. Continued development of effective humanized models will further propel our understanding of CDD biology and may permit the development and testing of therapies that will significantly alter CDD disease trajectory in young children.CDKL5 deficiency disorder (CDD) is an X-linked brain disorder of young children and is caused by pathogenic variants in the  Cyclin-dependent kinase-like 5  was identified as the disease-causing gene in 2004 . EL. EL86]. ll lines . ELOA hall lines . ELOA lill lines . Physiolll lines . DSBs arll lines . CDKL5-dll lines , elevatell lines .CDKL5 deletion are hypersensitive to DNA-damage induced stress and showed DNA damage-associated markers , reduced cell viability and impaired neuronal maturation . Th. Th59]. in vivo [CDKL5 is a shootin1 (SHTN1)-interacting protein identified using yeast-two hybrid screening, with this interaction confirmed in vivo . SHTN1 hin vivo . Althoug631  at Ser631 , but notcontacts , which mCdkl5 knockout mice there is increased apoptosis of post-mitotic granule neuron progenitors and severe dendritic hypotrophy [CDKL5 promotes the proliferation and differentiation of neuronal cells by regulating cell cycle progression , and knopotrophy . CDKL5 cpotrophy . In the potrophy ,44,46, hpotrophy  and DNA potrophy . Both Mepotrophy  and CDKLpotrophy , which a199 is not within the CDKL5 consensus motif, this phosphorylation event reduced the stability of the SOX9 protein. Although the role of SOX9-mediated phosphorylation by CDKL5 has not yet been explored in neurons, phosphorylation modification of SOX9 has a critical role in neural crest delamination [Increasing evidence highlights CDKL5 as kinase involved in stress response. Recently, a potential non-neuronal function of CDKL5 was identified in a kinome-wide screen in renal tubular epithelial cells. CDKL5 was found to phosphorylate the transcription factor SRY-box transcription factor 9 SOX9;  and suppmination  which isCdkl5 KO neurons, providing evidence for a potential new therapeutic target for CDD [Another identified phosphorylation target of CDKL5 is the transcriptional factor SMAD3, although the exact phosphorylation site remains undetermined. Direct phosphorylation of SMAD3 protein by CDKL5 promotes SMAD3 stability, conversely, reduced SMAD3 levels impaired neuronal survival and maturation . This ob for CDD .CDKL5 variants, understanding CDKL5 signaling pathways will have broad implications for understanding neurodegenerative disorders, in particular the fundamental importance of kinase-regulated signaling pathways in the brain. By translating and implementing such fundamental scientific research findings, an in-depth knowledge will have the power to rapidly deliver new therapeutics to transform the health of children who would otherwise suffer a devastating progressive disease trajectory because of CDKL5 deficiency.The compromised ability of specific kinases to regulate intracellular signaling networks commonly underlies disease pathogenesis, particularly in neurological conditions. However, understanding the disrupted signaling pathways poses a fundamental challenge in neurobiology. Therefore, it is essential we understand the molecular pathways and the phosphorylation targets of CDKL5 and how this relates to CDD pathophysiology, progression and disease sub-types. In-depth knowledge of molecular pathways regulated by CDKL5 may reveal druggable targets which could be exploited to fast-track the development of targeted therapeutics that address directly, the molecular cause of CDD. We anticipate that in addition to directly benefitting patients with pathogenic CDD is a serious health condition, current treatment and existing therapies target disease symptoms, rather than addressing the underlying abnormal biological processes. There is an urgent need to advance our understanding of CDD biology so that we can test therapies that might significantly alter the CDD disease trajectory in young children.Whilst the progressive nature of CDD provides an excellent opportunity for disease intervention, without an intimate knowledge of CDKL5 function and phosphorylation targets we cannot effectively develop new effective therapeutics. By understanding the cellular targets of CDKL5, we can direct the development of therapeutics specifically towards these targets. This is necessary before significant progress can be made in the development of novel targeted therapies.The identification of new CDKL5 targets that modulate aberrant neuronal activity in CDD will likely have broader implications for other severe neurological disorders.


Background and aim: Inflammatory diseases that affect the outer retina do so by different mechanisms. Some of them result from the direct, primary involvement of the outer retina (primary photoreceptoritis) such as acute zonal outer occult retinopathy (AZOOR). Others affect the photoreceptors secondarily due to the inflammatory involvement of the choriocapillaris. This results in choriocapillaris non-perfusion that damages the photoreceptors due to the ensuing ischaemia, a mechanism characterising primary inflammatory choriocapillaropathies (PICCPs) such as multiple evanescent white dot syndrome (MEWDS), idiopathic multifocal choroiditis (MFC), and others. Thanks to multimodal imaging (MMI), it is now possible to differentiate between these two mechanisms of outer retinal damage. The aim of this study is to determine the MMI characteristics that allow us to differentiate primary photoreceptoritis, including AZOOR, from PICCPs such as MEWDS and MFC. Methods: A series of eight PICCPs cases  and four typical primary photoreceptoritis/AZOOR cases (five eyes) that had undergone complete MMI investigation, including fundus photography (FP), blue light fundus autofluorescence (BL-FAF), spectral domain optical coherence tomography (SD-OCT), OCT angiography , fluorescein angiography (FA), and indocyanine green angiography (ICGA) were analysed, pointing out the differences that allow us to distinguish primary photoreceptoritis from PICCPs. Results: All primary photoreceptoritis/AZOOR cases showed (1) faint fundus pallor around the fovea, (2) BL-FAF hyperautofluorescence, (3) loss of photoreceptor outer segments (PROS) on SD-OCT, (4) absence of choriocapillary drop-out on OCT-A, (5) normal FA or faint FA hyperfluorescence, and (6) conserved ICGA fluorescence/no hypofluorescent areas; (1), (2), (3), and (5) indicated loss of photoreceptor outer segments, and (4) and (6) indicated conserved choriocapillaris circulation. For PICCPs, (a) fundus showed discreet white dots or none (in MEWDS) and punched-out scars in MFC, (b) BL-FAF hyperautofluorescence, (c) loss of PROS on SD-OCT, (d) FA faint hyperfluorescence in MEWDS, also minimal in active MFC lesions (e) in all cases ICGA hypofluorescent areas; (b) and (c) indicating loss of PROS, and (e) indicating choriocapillaris non-perfusion in all cases. The OCT-A did not show consistent findings with faint or no capillary drop-out in MEWDS and MFC. Conclusions: MMI combining the SD-OCT and BL-FAF clearly showed loss of PROS in both groups, while the ICGA determined whether this was due to choriocapillaris non-perfusion in PICCPs or whether the choriocapillaris was intact in case of primary photoreceptoritis. The FA and OCT-A were found to be less useful and/or less sensitive for the appraisal of both these entities. The outer retina is a watershed region depending mostly on the choriocapillaris for its supply of oxygen and nutrients rather than from retinal circulation. Furthermore, structures like the photoreceptors are very vulnerable and easily damaged by hypoxemia, as these cells are metabolically very demanding . A lack Inflammatory diseases producing damage to the outer retina have been characterised with difficulty in the past. Their classification was not clear before multimodal imaging (MMI) became available and could better identify the structures involved and the sequence of events.At least two main types of lesion processes can be identified. On one side, photoreceptors can be damaged secondarily, the main mechanism for this being inflammatory choriocapillaris non-perfusion (choriocapillaritis) producing ischaemia on the RPE-photoreceptor complex, as explained hereabove. The gold standard to detect even minimal choriocapillaris non-perfusion and characterise primary inflammatory choriocapillaropathies (PICCPs) is indocyanine green angiography (ICGA) . The degOn the other hand, photoreceptors can be damaged primarily and the condition can then be called primary photoreceptoritis. The mechanisms leading to primary photoreceptoritis are much less known and rely mostly on conjectures. Acute zonal outer occult retinopathy (AZOOR) is one condition causing primary photoreceptoritis . InflammIn the past, it was not always possible to determine the pathophysiological process in diseases of the outer retina, and choriocapillaritis as well as primary photoreceptoritis were entities classified together by several authors, including Gass, who thought they were variants of the same autoimmune disorder that he called the “AZOOR complex disorders” ,9,10,11.Thanks to MMI, it is now possible to distinguish the diverse mechanisms involved in outer retinal disorders and the aim of this case series is to practically demonstrate the contribution of imaging to precisely illustrate, analyse, and classify the inflammatory diseases of the outer retina.®, Optovue, Fremont, CA, USA). Best corrected visual acuity (BCVA), visual field recording using the Octopus G program  and/or microperimetry  were performed. Investigations were centered only on MMI findings at presentation without details on treatment and evolution.In this retrospective study, patients seen in the Centre for Ophthalmic Specialised care, from 2012 to 2018, with inflammatory outer retinal pathology characterised by damage or loss of photoreceptor outer segments including MEWDS, MFC, and AZOOR-like outer retinopathy, and had been investigated by MMI were included. Patients with low-quality images or with incomplete MMI were excluded. Imaging analysis included fundus photography, fluorescein angiography (FA), indocyanine green angiography (ICGA) spectral domain optical coherence tomography (SD-OCT), blue-light fundus autofluorescence (BL-FAF) , and OCT angiography  . Visual field impairment was very diverse from one patient to another in both groups. The mean of the mean defect (MD) was 5.27 ± 3.9 dB in the MEWDS + MFC group versus 17.64 ± 8.45 dB in primary photoreceptoritis, which was highly statistically different .Five patients diagnosed with MEWDS (three men and two women), three MFC patients , and four patients (five eyes) (three women/one man) diagnosed with primary photoreceptoritis were included in the study. The mean age at presentation was 39.4 ± 13.6 years and there was no significant difference in age between the two analysed conditions. The BCVA (Snellen) at presentation was 0.73 ± 0.28  in the MEWDS + MFC group, and 0.48 ± 0.41 SD in the photoreceptoritis group (NS). There was no significant difference in BCVA among both groups . Multimodal imaging of patient No. 1 is illustrated in MEWDS case 2A 39-year-old man presented with a history of photopsias in his left eye. The BCVA was 1.0 and visual field impairment was moderate with a mean defect (MD) of 4.1 dB.MEWDS case 3A 46-year-old woman presented with blurry vision and photopsias. The BCVA was 0.9. Visual field impairment was severe with an extensive centroceacal scotoma with a mean defect (MD) of 13.6 dB.MEWDS case 4This 31-year-old lady presented typical symptoms of photopsias and subjective visual field disturbance. MEWDS case 5This 27-year-old man presented a fluctuating subjective scotoma in the last 10 days and signaled blurred vision in his right eye. The BCVA was 0.6. There was minimal visual field impairment with a mean defect (MD) of 2.6 dB but a loss of retinal sensitivity on microperimetry, reduced to 320/560.MFC case 1® 2 × 720 mg), and cyclosporine (150 mg/d). Four months later she complained of photopsias OS with multimodal imaging showing a new episode of MFC OS  of 7.2 dB. Multimodal imaging is shown in MFC case 3® G1 program showed a scotoma corresponding to the BL-FAF hyperautofluorescent/ICGA hypofluorescent area (bottom middle-left).A 46-year-old woman presented rapidly when she noticed photopsias OD. She was very well aware of the symptomatology, as she had been treated with triple immunosuppressive therapy for MFC in her left eye for three years, seventeen years previously. The BCVA OD was 1.0 but there was a moderate visual field impairment with a mean defect (MD) of 6.0 dB. The presentation was typical for a new episode of MFC. Multimodal imaging of the case is illustrated in In some active MFC cases, SD-OCT presented hyperreflective-cone shape lesions. In case the IS/OS zone was not disrupted by these lesions and the patient was treated properly, these lesions resulted in the maintenance of a healthy IS/OS line . The BCVA was 0.8. Multimodal imaging, illustrated in Photoreceptoritis case 2This 56-year-old woman was sent for a second opinion because of a visual field loss (MD = 6.2 dB) with a conserved BCVA of 1.0. Multimodal imaging is illustrated in Photoreceptoritis case 3This 46-year-old man complained of a sudden complete visual loss in his right eye. His vision was reduced to hand movements and he presented a severe visual field defect (MD = 19.6 dB).Multimodal imaging illustrates the lesions in Photoreceptoritis 4 and 5This 44-year-old woman was sent to us for second advice by her uveitis specialist. She had consulted for bilateral photopsias, decreased contrast sensitivity, photophobia, and scotomas without any overt intraocular inflammation. At presentation, the BCVA was 0.2 (OD) and 0.4 (OS). Her visual fields were tubular (MD OD = 21.7 dB and MD OS = 21 dB).Fundus examination showed faint discoloured rings OU around the central maculae . NoteworThe MMI findings in eight cases of choriocapillaritis, including five MEWDS and three MFC patients, compared to three primary photoreceptoritis patients (four eyes) are summarised in p = 0.13, Student’s t-test), but visual field loss was significantly more important in the photoreceptoritis group with a mean of MD of 17.64 ± 6.45 dB versus 5.27 ± 3.9 dB in the choriocapillaritis group . In the photoreceptoritis patient of case No. 4, both eyes showed a bright hyperautofluorescent ring around the central normal area, possibly indicating disease activity causing increased production and/or decreased clearance of lipofuscin by the RPE [Fundus findings were all characteristic of their respective diseases: white dots or foveal granularity for MEWDS, punched-out small scars for MFC, and perifoveal pale fundus halos for four out of the five cases of photoreceptoritis eyes, which was interpreted as annular loss of photopigment due to the loss of photoreceptor outer segments. The BL-FAF hyperautofluorescence was found in all 13 eyes together with loss and/or damage of IS/OS line on the SD-OCT, indicating a loss of photoreceptor outer segments in all cases. Most of our photoreceptoritis cases presented the characteristic tri-zonal pattern in the zone of transition from the healthy to the diseased area, shown in SD-OCT and BL-FAF; some studies presented this as a demarcating line of the progression at the level of the outer retina and a trizonal pattern of sequential involvement of the outer retina, retinal pigment epithelium, and choroid . The onlInflammatory damage to the outer retina has been ill-understood and classified indistinctly in the same pathology group, as thought by many including JD Gass ,9,10,11.The choriocapillaritis entities have been well-defined, although some divergent views still exist as far as MEWDS is concerned ,16,17,18On the other hand, primary photoreceptoritis is due, at least for a substantial proportion of cases, to inflammatory causes, as several articles report the efficacy of corticosteroids and/or immunosuppressants in their treatment ,22,23,24Unfortunately, nowadays, many MMI studies do not include ICGA anymore, the only modality able to detect choriocapillary non-perfusion including the small low-flow end-capillary choriocapillaris vessels; therefore, differentiation between choriocapillaritis and photoreceptoritis is not possible. This is also the reason why MEWDS has been falsely interpreted as a photoreceptoritis ,27,28,29Although the mechanisms in choriocapillaritis and primary photoreceptoritis fundamentally differ, the occurrence of both conditions in the same patient has been described ,30,31,32Usually, neither mild choriocapillaritis nor photoreceptoritis fatally damages the RPE cells, which are metabolically resistant . For insThe functional consequences, especially in visual field defects, are much more substantial in photoreceptoritis compared to choriocapillaritis; this can be explained by the fact that the photoreceptors are not directly the aim of the pathological process, but are only secondarily involved following perfusion problems of the choriocapillaris. Moreover, when looking at the literature, corticosteroid/immunosuppressive therapy seems to be more efficient in choriocapillaritis (for those conditions that need therapy) than in photoreceptoritis, where mixed results have been reported ,35.In summary, MMI allows us to differentiate more clearly the pathophysiology of outer retinal diseases. The determining imaging modality that allows us to distinguish between photoreceptoritis and choriocapillaritis is ICGA.


Alcohol consumption was also identified as a risk factor for high-risk colorectal neoplasia. In conclusion, severe hepatic steatosis on FibroScan is associated with the development of high-risk colorectal neoplasia. Thus, physicians should be aware of the association between colorectal neoplasia and hepatic steatosis assessed by FibroScan and its clinical implications.The prevalence of colorectal neoplasm in patients with non-alcoholic fatty liver disease has increased twice as high as that in the general population. FibroScan is a new modality for evaluating hepatic steatosis. This study aimed to investigate the relationship between the risk of high-risk colorectal neoplasia and hepatic steatosis examined using FibroScan. This was a cross sectional study of prospectively enrolled subjects who were scheduled to undergo index colonoscopy as a health screening between March 2018 and February 2019. The severity of steatosis was graded as normal, mild, moderate, or severe using FibroScan. A total of 140 consecutive subjects were enrolled and sequentially examined using FibroScan and colonoscopy. Subjects with hepatic steatosis had more high-risk colorectal neoplasia than those without hepatic steatosis. In addition, tumor size was larger in subjects with hepatic steatosis. In multivariable analysis, severe hepatic steatosis was an independent risk factor for high-risk colorectal neoplasia (adjusted odds ratio: 3.309, confidence interval: 1.043–10.498,  Colorectal cancer is the third most prevalent cancer and the second most common cause of cancer-related mortality worldwide, respectively . The adeNon-alcoholic fatty liver disease (NAFLD) is a risk factor for colorectal cancer and adenoma –17. PrevLiver biopsy is the gold standard for evaluating hepatic steatosis and fibrosis. However, it is invasive and can cause complications, such as massive bleeding. Abdominal ultrasonography is the standard modality for evaluating NAFLD; however, it is a subjective procedure and thus has limitations due to inter-observer variation . FibroScThus, this study aimed to evaluate the relationship between the risk of colorectal tumorigenesis examined by index colonoscopy and hepatic steatosis examined by FibroScan.This was a cross sectional study of prospectively enrolled subjects who were scheduled to undergo index colonoscopy as a health screening between March 2018 and February 2019 at Seoul National University Boramae Hospital, Seoul. Consecutive subjects aged 40 to 75 years who underwent a healthcare screening exam not related with symptom of colitis, bleeding or drug history at Seoul National University Boramae Hospital were screened. The exclusion criteria were (1) previous colonoscopy, colon study, or computed tomographic colonography; (2) history of colorectal cancer or inflammatory bowel disease such as ulcerative colitis and Crohn’s disease; (3) previous colectomy for any cause; or (4) history of liver disease , liver cirrhosis of any cause, alcoholic liver disease, or autoimmune hepatitis.The study protocol was approved by the Institutional Review Board of Seoul National University Boramae Hospital (Protocol number: 30-2018-18) and was conducted according to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all enrolled patients.Detailed history taking, electronic medical record search, and laboratory examinations were performed at the first visit. History taking included age; sex; body mass index (BMI); alcohol consumption; smoking; underlying diseases such as hypertension, diabetes, liver disease, and gastrointestinal disease; and history of surgery, colonoscopy, or radiologic examination. Laboratory examination included complete blood count, chemistry, and serological tests such as hepatitis B and C viruses.2). BMI ≥ 23 kg/m2 was classified as overweight or obese according to the Asia-Pacific BMI criteria established by the Western Pacific Region of the World Health Organization [BMI was calculated as weight (kg) divided by height (m) squared  using CF- and CF-H colonoscopies . The procedure was performed under conscious sedation with intravenous midazolam and intramuscular pethidine. The subjects were given polyethylene glycol for bowel preparation with detailed instructions.A complete colonoscopic examination was defined as reaching the medial side of the ileocecal valve, as documented by endoscopic imaging. The withdrawl time of colonoscopic evaluation was at least 6 minutes to minimize the probability of missing lesions. Incomplete colonoscopic examinations were excluded from the analysis. Images of all examined colorectal lesions were collected to determine the total number of lesions, locations, and sizes. The quality of bowel preparation was graded using the Boston Bowel Preparation Scale . ProceduColorectal adenomas were confirmed by pathologic evaluation after colonoscopic tissue biopsy or mucosal resection. A diagnosis of total colorectal neoplasia was made if the lesion was confirmed as adenoma or cancer, irrespective of other findings such as size, number, dysplasia, and detailed histology. High-risk colorectal neoplasia was defined as advanced colorectal neoplasia or ≥ 3 colorectal adenomas. Advanced neoplasia was defined as advanced adenoma or colorectal cancer. Advanced adenoma was defined as the presence of one or more of the following features: (1) largest diameter ≥ 1 cm, (2) including tubulovillous or villous histology confirmed by pathologic examination, and (3) high-grade dysplasia confirmed by pathologic exam . Serrate3, respectively.FibroScan was used evaluate hepatic steatosis and fibrosis, which were graded by severity . The exaThe quantitative values of steatosis and fibrosis were measured according to CAP and liver stiffness measurement (LSM), respectively. FibroScan measures LSM and CAP based on vibration-controlled transient elastography (VCTE). For LSM, VCTE uses pulse-echo ultrasonic acquisition to quantify the speed of shear waves induced in liver tissue; for CAP, ultrasonic attenuation of the echo wave is acquired ,29. The The primary outcome measure was the correlation with high-risk colorectal neoplasia according to the severity of hepatic steatosis because high-risk colorectal neoplasia requires surveillance colonoscopy in 3–5 years, which is earlier than the usual schedule . AdditioContinuous variables were expressed as the means with standard deviations or as percentages, as appropriate. Categorical variables were expressed as numbers or as percentages, as appropriate.2 test, as appropriate. Univariable and multivariable logistic regression analysis were performed to assess the interaction between the dependent variables of colorectal adenomas and the independent variables including test results of hepatic steatosis, age, sex, BMI, smoking, alcohol consumption, underlying diseases, family history of colorectal cancer, and related laboratory results. Each odds ratio (OR) is presented together with its 95% confidence interval (CI). All statistical analyses were performed using the Statistical Package for Social Sciences version 25.0 . Statistical significance was defined as a two-sided p value of < 0.05.Categorical variables were compared using one-way ANOVA or χOf the 155 consecutive subjects who were enrolled before the endoscopic procedure, 15 patients were excluded because they did not undergo FibroScan or colonoscopy. Finally, a total of 140 consecutive subjects who underwent index colonoscopy for screening were enrolled and evaluated using FibroScan. The mean subject age was 59.2 years , and there were 63 (45%) and 77 (55%) female and male subjects, respectively. There were 49 subjects (35%) who were current alcohol drinkers.The population was initially categorized as having steatosis, as measured by FibroScan. Subjects with S1 or higher steatosis were categorized into the steatosis group, while subjects with normal values were categorized into the normal group. There was no significant between-group difference in age, sex, height, smoking, underlying diseases, family history of colorectal cancer, and laboratory test results. However, body weight and BMI were significantly different between the two groups. HDL levels were significantly lower in the steatosis group. ALT and TG levels were significantly higher in the steatosis group. The baseline subject characteristics by steatosis grade are shown in All data on hepatic steatosis and fibrosis were assessed using FibroScan and are summarized in p = 0.016). The rate of high-risk colorectal neoplasia was also higher in subjects with severe hepatic steatosis (44%) than in subjects with normal (20%) or mild to moderate hepatic steatosis (30%). Overall, 3 (2.1%) subjects were diagnosed with colorectal cancer. The colonoscopic findings are summarized in In total, 74 (53%) subjects had one or more adenomas. There was no significant difference in the rate of total colorectal neoplasia between the two groups. However, there was a significant difference in high-risk colorectal neoplasia and non-advanced adenoma. In addition, subjects with hepatic steatosis had larger adenomas   .Hepatic steatosis and colorectal neoplasia may be associated by sharing common factors such as insulin resistance by metabolic syndrome and altered gut microbiome –32. HoweColon tumorigenesis comprises three processes: initiation, promotion, and progression. The role of hepatic steatosis in colon tumorigenesis remains unclear. However, previous studies have demonstrated that fat accumulation in hepatocytes can lead to an inflammatory state in the liver. Hepatic steatosis can then induce or accelerate the disruption of the gastrointestinal tract via pro-inflammatory cytokines  that promote tumor formation in the colon . It alsoIn our study, the prevalence of total colorectal neoplasia did not differ significantly according to the presence of hepatic steatosis, suggesting that hepatic steatosis is not associated with tumor initiation in colorectal tumorigenesis. However, there were significant differences in high-risk colorectal neoplasia and non-advanced adenoma between the steatosis and normal groups. Moreover, the average tumor size was greater in the steatosis group, suggesting that hepatic steatosis may be associated with tumor promotion in colorectal tumorigenesis. Further studies are needed to elucidate the basic mechanism of the effect of hepatic steatosis on colon tumorigenesis and the therapeutic effect of hepatic steatosis on colorectal tumor promotion.We demonstrated that alcohol consumption was an independent risk factor for high-risk colorectal neoplasia. This is in line with a previous report by Terry et al. that alcohol consumption could be a risk factor for advanced colorectal adenoma . Song etIn general, colorectal cancer screening is recommended for subjects aged ≥ 50 years. However, colonoscopy as the reference standard for detecting precancerous lesions and colorectal cancer is an intensive procedure, requiring bowel preparation and having risks of various complications such as abdominal discomfort, pain, and perforation. In addition, colonoscopy is expensive, which may cause a delay in colorectal cancer screening. Therefore, it is crucial to know the risk factors for high-risk colorectal neoplasia. FibroScan is an easy procedure with high reproducibility. It also has the advantages of providing more information than does liver biopsy by acquiring images of a larger liver volume and being non-invasive, requiring only a probe to touch the skin. Severe hepatic steatosis is prevalent in 24.2% of the general population. In this study, approximately half of the subjects with severe hepatic steatosis had high-risk colorectal neoplasia. This indicates that physicians should recommend the individuals with severe hepatic steatosis for colonoscopy for colorectal cancer screening rather than other alternative methods.Our study has several strengths. To our best knowledge, this is the first study to explore the impact of hepatic steatosis assessed using FibroScan on the risk of colorectal neoplasia in the general screening population who underwent their first colonoscopy during lifetime. Our results provide further evidence on the role of severe hepatic steatosis in colon tumorigenesis, and our protocol overcomes the bias in previous studies. Second, all subjects were studied per standardized study protocol and only subjects with NAFLD were included, while those with hepatitis-related confounding factors such as viral infection or autoimmune disease were excluded. This allowed us to explore the independent role of hepatic steatosis in colon tumorigenesis. Third, we evaluated confounding factors including smoking, BMI, family history of colorectal cancer, and underlying diabetes. Finally, all polyps identified during the study were removed and histologically evaluated by pathologists. Therefore, our study provides a robust causal relationship between severe hepatic steatosis and high-risk colorectal neoplasia.However, our study had some limitations. First, this was a single-nation, single-race, single-center study, and thus, the results may have limited generalizability. Second, the study population was not large and we could not evaluate confounding factors such as abdominal visceral adiposity and show more clear statistical values in various aspects of colorectal neoplasia. Third, there was few data about advanced liver fibrosis, the relationship between the liver fibrosis measured by Fibroscan and colorectal neoplasia could not be statistically evaluated. In addition, although hepatic steatosis examined by FibroScan was well correlated with the result of liver biopsy, the possibility of selection bias is unavoidable because the prevalence of moderate to severe hepatic steatosis in this study is higher than that in the general population ,37–39. FIn conclusion, severe hepatic steatosis on FibroScan is significantly associated with high-risk colorectal neoplasia by index colonoscopy. Therefore, physicians and endoscopists should be aware of the association between colorectal neoplasia and hepatic steatosis assessed using FibroScan and its clinical implications.S1 Data(XLSX)Click here for additional data file.


This study aimed to determine hearing thresholds in an otologically normal population without occupational noise exposure aged 18 to 64 years using extended high-frequency audiometry (EHFA).Individuals from the general population who have never had hearing problems and whose job was not associated with noise exposure were included in the study and classified by age into 5 categories: 18–24 and, further, by 10 years of age. Each of these groups was further divided according to gender. All subjects underwent tympanometry, conventional pure-tone audiometry within the 0.125–8 kHz range, and extended high-frequency audiometry within the 9–16 kHz range, performed according to the standards. The significance level for statistical testing was set at 5%.Here, we established hearing thresholds in an otologically healthy population within the extended high-frequency (EHF) range (9–16 kHz). We found the EHFA to be a highly sensitive method for early detection of hearing loss, with hearing thresholds decreasing as soon as 35 years of age. In males, the hearing thresholds grew with age more rapidly than in women. The ability to respond at EHF gradually decreased with age and increasing frequency.Our results can help improve the knowledge of EHF hearing thresholds for individual sexes and age groups. So far, the standard 7029:2017 is not binding and, moreover, it only reaches up to the frequency of 12.5 kHz. EHFA is a highly sensitive method for the evaluation of hearing loss depending on age and sex. Hearing impairment is globally a highly topical issue. Nearly 2.5 billion people worldwide will be living with some degree of hearing loss by 2050, warns the World Health Organization’s (WHO) first World Report on Hearing. At least 700 million of these people will require access to ear and hearing care and other rehabilitation services unless action is taken . HearingAeq,8 h < 80 dB), randomly selected from the database of the facility who were not previously patients of the ENT clinic were offered participation. The study group was drawn from the socially consistent general population living in the same industrial region burdened also with traffic noise. Statistical evaluation was then limited only to data from participants whose tympanic membrane was assessed to be normal during otoscopic examination, whose immittance test of the middle ear (type A tympanometry curve) was normal and hearing loss at frequencies of 0.5; 1; 2; and 4 kHz was lower than 25 dB. The history of noise exposure in public areas and leisure activities was not investigated in this work; however, professional exposure to workplace noise was an exclusion criterion. The recruited individuals were divided into age categories of 18–24, 25–34, 35–44, 45–54, 55–64 years. The exclusion criteria were as follows: disagreement with inclusion in the study or with signing informed consent, age outside the range of 18–64 years, professional noise exposure, pathological result of an otoscopic examination, type B or C tympanometric curve, or hearing threshold of more than 25 dB at 0.5, 1, 2, or 4 kHz.This study was performed in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the University of Ostrava. All individuals completed and signed an informed consent form prior to inclusion in the study. The data were collected between 2020 and 2021 at the ENT outpatient clinic, which was a part of a multidisciplinary facility. Only individuals who have never had any hearing problems, self-assessed their hearing as “normal” and neither otoscopy nor tympanometry revealed any abnormalities were included in the study. The study group consisted of individuals aged 18–64 years who worked in a job without professional noise exposure , conventional pure-tone audiometry, and high-frequency audiometry , performed according to the standards EN ISO 8253-1:2010 Acoustics—Audiometric test methods and EN ISO 266:1997 Acoustics—Preferred frequencies . These sU test. Statistical significance was analyzed using the Stata version 13 software . The significance level for testing was set at 5%.The study results were exported to Microsoft Office Excel 2017  for calculation of basic descriptive statistics and to create tables and graphs. Data were analyzed using basic descriptive statistics, Pearson’s chi-squared test and the nonparametric Mann–Whitney p = 0.928; Table In all, 316 participants  aged 18–64 were included in the study, of which 68% were women and 32% men, respectively. There was no difference in the sex distribution among age groups  for both sexes. The results of this work can significantly contribute to the current knowledge at EHFas at present, the standard EN ISO 7029:2017 has only informative value for this range with a maximum of 12.5 kHz , 18.–64 for bOur results imply that it is important to distinguish between sexes but not between the right and left ears as the results for both sides are similar. This is in agreement with the study by Barbosa de Sá who reported that the thresholds were similar in the left ear and right ear, with significant differences between the ears only being observed at 11 kHz and 12 kHz, at which the right ear performed worse .Valiente et al. analyzed a group aged 5–90 with groups of 5–19 and, afterward, groups of 10 years of age. The mean hearing thresholds at each frequency (11.2 to 20 kHz) were lower in women than in men . This agWang et al. showed that hearing at EHF started to degenerate in subjects at their 30 s and the degeneration intensified in their 50 s and older age. The hearing thresholds of EHF were less than 26 dB before 30 years of age; with aging, however, the mean threshold values increased up to 75 dB . In our The ability to respond at EHF gradually decreased with age and increasing frequency up to 48% and 53% at 16 kHz in men and women in the age category of 55–64 years, respectively. However, at the frequency of 12 kHz, this parameter remained high even at the highest age group (99% women and 98% men). Our results indicate a higher ability to respond to EHF than the aforementioned Chinese  studies.Only a few published studies have used EHF to determine hearing thresholds in a professionally unexposed population. The comparison between studies is, however, often difficult due to differences in age groups, sex representation, evaluation of risk factors, or, possibly, used audiometers and their accessories (papers originate from 2001 to 2021) , 20. StuIn this study, hearing thresholds at various frequencies , age groups, and in both sexes were measured in a healthy population to propose normal hearing thresholds in the Central European population. In addition, we found that EHFA is a highly sensitive method for early capture of hearing loss. Hearing thresholds begin to deteriorate since 35 years of age; for this reason, individuals with a higher risk of hearing loss should be diagnosed at such an early age. In our study, we confirmed the differences in hearing thresholds between men and women while the differences between the right and left ears were statistically insignificant. In men, the hearing thresholds grew significantly faster than in women.


Exposure to noise is a common and the most preventable cause of hearing loss. Occupational noise is responsible for approximately 16% of disabling hearing loss in adults. Noise-Induced Hearing Loss (NIHL) is the second most common occupational illness or injury, even after decades of study, regulation and interventions in the workplace to try to prevent it.NIHL is irreversible, manifesting first and predominantly at the frequencies of 3 kHz, 4 kHz and 6 kHz. It takes longer for the frequencies of 0.25 kHz, 0.5 kHz, 1 kHz, 2 kHz and 8 kHz to be compromised.2NIHL etiopathogenesis is a multifactorial one. Several genes are involved in different mechanisms that increase susceptibility to noise.Risk awareness must be associated with patient motivation to take the necessary measures to reduce exposure to potentially harmful noise, both in the workplace and during leisure activities.Listening to music during sports activities increases attention, reduces fatigue and increases alertness. The effects obtained on performance depend on the characteristics of the stimulus, the individual and the intensity and type of activity. The more pleasant a song is, the louder you want to hear it.The appropriate frequency of occupational audiometric tests is poorly studied, and it is not based on population studies. There is general medical agreement that it audiometry should be performed annually. Brazilian legislation is the only one that establishes that the first periodic audiometric examination must be performed after six months of work, becoming annual as of the second periodic examination.Although the improvement in the standards and control of exposure to noise have advanced since the end of World War II, NIHL remains a significant public health problem. The problems caused by NIHL go beyond the auditory symptoms and may affect the vestibule, which increases the risks of accidents in the workplace, in addition to insomnia, irritability and arterial hypertension, decreasing productivity and resulting in risks to the workers’ health. There is much to be done to prevent the condition in populations that are genetically at greater risk for NIHL. The popularization of headphones to listen to music has resulted in early sensorineural hearing loss in young individuals and adolescents. It makes it difficult to identify workers whose audiometric thresholds have worsened exclusively due to their professional activity.The authors declare no conflicts of interest.