The associations between hearing loss and cognition are complex. Over the last decade, our understanding of some of the underlying mechanisms that contribute to this association have emerged. Additionally, more recent research has focused on the role of auditory rehabilitation on cognitive function. It is an exciting time to be a part of the interface of otologic medicine and surgery and cognitive hearing science research because of the rate at which knowledge is amassing in these disciplines. Each new idea represents a step forward and builds upon prior work. The breadth of this research is vast and involves a number of different research and clinical specialists that not only brings readers from the bench to the bedside, but also introduces them to ideas from surgeons to psychologists. With the range of specialists active in research of the associations of hearing loss and cognition, the field will likely continue to expand and evolve in a positive way. In this article collection we aim to highlight some of the ongoing research by demonstrating the breadth of the work.Jamsek et al. and Zhou et al. start by presenting research that explores the associations between executive function and cortical responses in children with hearing loss. van Wieringen et al. studied how sensorimotor and cognitive functions are coupled in mid- to late-adulthood. Jiang et al. evaluate the associations of audiometric hearing and speech-in-noise performance with cognitive decline in the aging population (>60 years old), and Burleson et al. explore the cognitive-linguistic abilities that contribute to perceptual restoration of degraded speech. Slade et al. present a meta-analysis of the impact of age-related hearing loss on structural neuroanatomy.With fifteen articles in the Research Topic and ninety-five authors, the included authors represent multiple countries spanning the globe. Beyond the diversity of our authors, the topics being researched are just as diverse, as are the types of research reported, from basic experimental research to applied science studies of patient and public involvement. Our authors present work that studies the association of hearing loss and cognition across the life span. Qiao et al. demonstrated central reorganization patterns in patients with single-sided deafness, while others explore bilateral hearing loss patterns. The impact of hearing aids  and cochlear implants  are assessed in various studies as well, along with the potential impact of cognition on device programming . Evolving forms of assessment of hearing loss and cognition in clinical populations are reported by Tarawneh et al. and Völter, Fricke et al.. Mathias et al. offer research that introduces the notion of genetic factors influencing the associations between cognition and hearing loss. Finally, Broome et al. explore patient perceptions of cognitive testing within the adult hearing service model.In addition to the impact of age on the association of hearing and cognition, the type of hearing loss and mode of intervention were explored in research for this article collection. This article collection covers incredible breadth and depth in the field of cognitive hearing science. As the fields of otology and cognitive hearing science continue to evolve and expand, so too will the collaborations that exist among clinicians and researchers. While our article collection brings clarity to a number of complicated questions related to hearing loss and cognition, it simultaneously blurs the distinction between surgeon, psychologist, and scientist. Similarly, the once clear-cut roles of the ear and the brain are becoming cloudy. The work we present to readers in this article collection represents a solid foundation on which future research can be established. We are fortunate to be involved in contributing to this foundation, and we are eager to see how this future evolves.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


Objective: To evaluate hearing outcomes at 2 years post endolymphatic duct blockage (EDB) surgery, with an analysis of factors that may predict hearing improvement. Study Design: Retrospective comparative study. Setting: Tertiary care center. Subjects: Definite Ménière’s Disease (MD) patients undergoing EDB for refractory disease. Methods: Chart review was conducted to assign cases to one of the three hearing outcome groups . All cases that met our inclusion criteria were selected. Preoperative data collected were audiograms, bithermal caloric tests, preoperative vertigo episodes, history of previous ear surgery for Ménière, intratympanic steroid injections (ITS) and intraoperative endolymphatic sac (ELS) tear or opening. Postoperative data collected at 24 months were audiograms, vertigo episodes and bithermal caloric testing. Results: Preoperative vertigo episodes, caloric paresis and history of surgery, ITS injections or ELS integrity, as well as postoperative vertigo class distribution and caloric paresis changes were not different between our groups. Preoperative word recognition score (WRS) was lowest in the improved hearing group (p = 0.032). The persistence of tinnitus at 2 years postoperatively was associated with deteriorated hearing (p = 0.033). Conclusions: There are no strong predictors of hearing improvement on presentation pre-EDB, but low preoperative WRS may be the best estimator available. Therefore, ablative interventions should be considered very carefully in patients presenting with low WRS, as they may benefit more from EDB; there is a fair chance of a good hearing outcome with EDB surgery. Persistence of tinnitus can reflect deteriorating audition. Vertigo control and hearing preservation are independent outcomes of EDB surgery, making it desirable as an early intervention for refractory MD cases. Ménière’s Disease (MD) is characterized by episodic vertigo, fluctuating sensorineural hearing loss, aural fullness, and tinnitus, with an incidence of 15–50 per 100,000 ,3. Low-fRefractory MD has been challenging for otologists as there is no consensus on the efficacy of surgery to this day ,6,7,8,9.Surgery for refractory MD lacks evidence in the literature for many reasons: poorly designed trials, difficulty in establishing control groups, variable diagnostic criteria and different reporting methods. MD’s natural course further complicates outcome reporting: in the early years following the first vertigo episode, fluctuating hearing loss is more common as well as MD attacks. In the later stage of the disease, hearing loss stabilizes while vertigo becomes less frequent and may even subside completely. Unilateral and bilateral MD also affect hearing differently; unilateral MD has a more severe effect on low frequencies, while bilateral disease is less severe but more often affects higher frequencies ,11,12,13Long term hearing outcomes are of particular interest with surgical treatment of MD because protecting patients from hearing loss over time has a considerable advantage, given that unlike vertigo, hearing loss is irreversible. In the literature, the different surgical techniques described result in a considerably wide range of outcomes: hearing improvement in 16–48% of cases ,18,19,20Despite the lack of convincing evidence for surgical interventions, less invasive alternatives, such as medical management or intratympanic injections, do not protect patients from hearing loss associated with the disease. Many studies report even higher hearing deterioration rates in the ranges of 15.5–62% ,24,25,26The objective of this study is to evaluate hearing outcomes at 2 years post endolymphatic duct blockage (EDB) surgery, with an analysis of factors that may predict hearing improvement.This is a retrospective single physician study, conducted at our tertiary care center following approval from our institutional IRB. Patients with a clinical diagnosis of definite MD, according to the 1995 AAO-HNS criteria ,29, and Diagnosis of definite MD;EDB surgery performed at our institution by the same surgeon;Age over 18 years old.Inclusion criteria:Incomplete records during the first 2 years post-EDB;Bilateral Ménière’s Disease;Disease onset more than 10 years before intervention;Nonfunctional affected ear or “dead ear” on presentation.Exclusion criteria:All eligible EDB cases were considered and grouped according to hearing outcomes, defined by variations larger than 15 dB for PTA or 20% for WRS . After applying our exclusion criteria, a total of 66 patients were included: 13 with deteriorated hearing, 15 with improved hearing and 38 with stable hearing.Demographic data included age and sex, reported as percentage of males. Preoperative parameters included a history of intratympanic steroid injections (ITS), a history of revision surgery, intraoperative ELS tear or opening, pure tone audiometry, vestibular caloric testing, aural fullness, tinnitus, and preoperative vertigo episodes (cumulative over 6 months). Postoperative parameters included pure tone audiometry, aural fullness, tinnitus, AAO-HNS vertigo class  28] and and28] aPure tone audiometry was performed on all patients at our tertiary care center’s audiology clinic. Average of hearing was calculated from hearing thresholds at 0.5, 1, 2 and 4 KHz and used for all analyses, including air conduction (PTA) and bone conduction (BCT). Word recognition scores (WRS) were recorded as the percentage of words repeated from a 25-word list at a comfortable hearing level. Audiometric testing was conducted the day before surgery and compared to the results obtained in the last 6 preoperative months; the worst audiogram was then selected for analysis. Postoperative testing was conducted at 2 years post-EDB. Vestibular caloric tests were performed in the 6 months before and during the first 6 months after EDB; bithermal testing was conducted for all cases at our institution. If the deficit affected the untreated ear, the value was reported as 0% for the operated ear.Age, preoperative vertigo episodes, PTA, BCT, WRS and caloric paresis are reported as means [95% confidence interval]. Sex, ITS injections, revision surgery, ELS integrity and vertigo class are reported as proportions (% of cases).p < 0.05 was considered statistically significant.Statistical analysis was completed using SPSS version 24 . The Shapiro–Wilk test was used to assess normality of each data set. One-way ANOVA was performed for continuous normally distributed variables. Intragroup testing for normal variables was conducted using paired T-tests. The Chi-square and McNemar tests were used for proportion distributions. For non-normally distributed data, the Kruskal–Wallis non-parametric test was performed, and intragroup testing was conducted using the Mann–Whitney test. p = 0.22). Sex distribution was also homogenous: 29% males in the stable hearing group, 43% males in the deteriorated hearing group and 50% in the improved hearing group (p = 0.343). Our groups were therefore adequately matched for analysis.Age and sex distributions are shown in Our cohort as a whole showed stable hearing at 2 years post-EDB: mean postoperative PTA was 55.2 [49.9–60.6] dB (mean increase of 5.1 dB over 24 months); mean postoperative BCT was 46.5 [41.2–53.7] dB (mean increase of 0.8 dB over 24 months); and mean postoperative WRS was 62.9 [56.1–69.6%] (mean increase of 1% over 24 months). Neither of those changes are clinically significant. p < 0.001) and the mean loss of word recognition was 25.7% (p < 0.001).The deteriorated hearing group had a mean postoperative PTA of 69.4 [61.9–76.9] dB, BCT of 42.9 [55.1–66.3] dB and a mean WRS of 45.8 [35.2–56.4%]. Over 24 months, the mean PTA increase was 20.6 dB (p = 0.02), with a mean loss of 1.4% on word recognition (p = 0.3).The stable hearing group had a mean postoperative PTA of 49.1 [39.9–58.4] dB, BCT of 42.9 [33.2–52.6] dB and a mean WRS of 63.4 [50.4–76.5%]. The mean increase over 2 years was 2.8 dB (p < 0.001) while the PTA showed a mean loss of 8.6 dB (p = 0.002). Finally, the improved hearing group had a mean postoperative PTA of 46.2 [37.3–55.1] dB, BCT of 39.5 [30.4–48.7] dB and a mean WRS of 80.1 [72.4–87.8%]. Over 2 years, the mean increase in word recognition was 28.3% . The cumulative number of vertigo spells in the 6 months before surgery was also similar between our groups (p = 0.17) with a mean 18 episodes in the stable hearing group, 32.14 in the improved hearing group and 28.15 in the deteriorated hearing group. Regarding bithermal caloric testing, preoperative caloric paresis was not significantly different between our groups (p = 0.29).Preoperative factors are shown in p = 0.523). However, preoperative WRS was significantly lower in the improved hearing group when compared to the other two groups (p = 0.032).The difference observed in preoperative PTA between our groups was not statistically significant (p = 0.38).Postoperative factors are shown in p = 0.22).Caloric paresis in the affected ears were not significantly changed after the intervention in any group, with mean improvements of 10.3% for all patients, 7.25% in the stable hearing group, 9.84% in the improved group and 11.4% in the deteriorated group (p = 0.647). However, persistence of tinnitus at 2 years was associated with a deteriorated hearing outcome: 76%, 82% and 100% of cases in the stable, improved, and deteriorated hearing groups, respectively (p = 0.033).Regarding symptoms, persistence of aural fullness at 24 months was not associated with any particular group: 71.4%, 60% and 70% of cases in the stable, improved and deteriorated hearing groups, respectively . Instead, WRS on presentation was significantly lower in the improvement group (p = 0.032), suggesting that even where WRS is low  there is a fair chance of a good hearing outcome. This is clinically relevant as poor functional hearing is often a reason to advocate a destructive procedure. Based on the data presented, we suggest ablative interventions, such as intratympanic Gentamycin injection, labyrinthectomy or vestibular neurectomy, should be considered very carefully with patients presenting with low WRS or even to be avoided, as they might benefit more from EDB. We can at least claim that EDB surgery is overall unlikely to have a severe negative impact on hearing. Long term outcomes cannot be extrapolated from this observation, as the fluctuating nature of hearing loss complicates this analysis. The ability to predict which hearing presentation is most likely to benefit from hearing improvement in MD after surgery would be an important asset to ENT surgeons: the decision to undergo EDB or other interventions, such as intratympanic Gentamycin injections or labyrinthectomy, can be better targeted. A long-term study for multiple procedures   concludep = 0.236, and p = 1, respectively). This suggests that hearing outcomes post-EDB are not affected by previous interventions and should not alter the management of EDB candidates. Furthermore, endolymphatic sac integrity during surgery, which can be difficult to maintain due to challenging dissection of the endolymphatic duct, has no impact on hearing outcomes (p = 0.141). This was reported too in 2016 by our team by using different data of patients [p = 0.17, and p = 0.29, respectively). The clinical implication is that hearing outcomes and symptoms control can be considered independently when evaluating a patient for surgery, making EDB an ideal procedure for refractory MD in the early disease phase. Regarding other preoperative factors, we could not find any that was particular to the improved hearing group. A positive history for intratympanic steroid injections or previous surgery for Ménière’s  was not associated with any hearing outcome (patients . Since np = 0.38), neither was any improvement in caloric paresis (p = 0.22). This is probably due to the very high rate of vertigo control irrespective of hearing outcome or functional status. Complete vertigo control (class A) and substantial control (class B) were achieved in 85% and 15%, respectively. Class A and B are considered as satisfactory control of vertigo and was obtained in 100% of cases at 2 years follow-up post-EDB. Since paresis of the vestibular function did not exceed 10% in the three groups, EDB can be established as a safe procedure for the labyrinth and could be considered as the preferred surgical choice for refractory disease. In the challenging treatment of Ménière’s, we have to also focus on the outcome of vestibular preservation, in addition to hearing preservation, since bilateral disease is frequent and can be developed in 30% of cases. The increased administration of ablative procedures puts many patients at a disadvantage if they develop bilateral Ménière’s later in life.In the follow up period of 2 years post-EDB, we were also interested in postoperative parameters that could be associated with hearing improvement. Vertigo control was not particular to any group (p = 0.647) but tinnitus was more prominent in the deteriorated hearing group (p = 0.033). This is likely due to the higher damage sustained by hair cells in that group.On the other hand, we also evaluated the persistence of aural fullness and tinnitus after 24 months: aural fullness was distributed similarly in our groups (This study has the limitations typically encountered in retrospective reviews as well as has a selection bias imposed by the research question. The impact of selection bias was reduced by including all eligible cases and statistically confirming the homogeneity of the samples. It is important to mention that all surgeries in this study were performed by a single surgeon and that overall good results might not be generalizable to other surgeons and units.Future research should include long-term follow-up of EDB cohorts to determine the long-term effect of surgery on hearing outcomes, ideally with comparison of matched controls on medical therapy.Endolymphatic duct blockage surgery is a safe and effective surgical option for treatment of MD, with excellent vertigo control, hearing preservation or improvement in most cases at 2 years. We could not identify strong predictors of hearing improvement on presentation, but a lower WRS in the interval 40 to 60% may be the best estimator available. Therefore, ablative interventions, such as intratympanic Gentamycin injection, labyrinthectomy or vestibular neurectomy, should be considered very carefully in patients with low WRS, as they may benefit more from EDB; there is a fair chance of a good hearing outcome with EDB. Vertigo control and hearing preservation are independent outcomes of EDB surgery, making it desirable as an early intervention for refractory MD cases.


Streptococcus bovis/Streptococcus equinus complex (SBSEC) bacteria is associated with underlying colorectal neoplasia. However, the link between intestinal or fecal colonization with SBSEC isolates or antibody responses to SBSEC members and colorectal cancer is not thoroughly investigated in the literature.Invasive infection with We searched the PubMed, EMBASE, and Web of Science databases for case–control studies as well as retrospective or prospective cohort studies reporting an association between SBSEC bacteria and colorectal neoplasia.We identified 22 studies (15 case–control and 7 cohort) that met our inclusion criteria. Among the cohort studies, patients with SBSEC bacteremia were 3.73 times more likely to have underlying colorectal cancer compared with individuals with no bacteremia , whereas the risk of underlying colorectal adenoma in patients with SBSEC bacteremia was not significantly increased . In case–control studies, patients with colorectal cancer were 2.27 times more likely to have evidence of intestinal or fecal colonization with SBSEC isolates  and immunoglobulin G (IgG) antibody responses to SBSEC antigens  compared with controls. Patients with colorectal adenoma were not more likely to be colonized with SBSEC isolates compared with controls .Apart from the well-established association of SBSEC bacteremia and underlying colorectal cancer, intestinal or fecal colonization with SBSEC isolates and IgG antibody responses to SBSEC antigens were higher in patients with colorectal cancer compared with controls. Neither bacteremia from SBSEC isolates nor colonization with SBSEC bacteria was associated with underlying colorectal adenoma. Streptococcus bovis/Streptococcus equinus complex (SBSEC) is a group of nonenterococcal group D streptococci that cause invasive disease, mainly bacteremia or infective endocarditis  and and28] aStreptococcus bovis” OR bovis OR gallolyticus OR infantarius OR pasteurianus OR coli OR lutetiensis) AND ). Manual checking of reference lists of retrieved articles and reports, including relevant papers and meta-analyses, was performed to identify additional and potentially relevant articles. The Rayyan screening tool was used to create our database and screen the exported studies [We searched the PubMed/MEDLINE, EMBASE, and Web of Science databases for literature in English  using the following search terms: ((“sodA gene via polymerase chain reaction (PCR) or in situ hybridization in colonic or fecal tissue samples; or (c) presence of IgG antibodies against the SBSEC cell wall and pili protein antigens in the serum  presence of SBSEC bacteremia and/or infective endocarditis, diagnosed via blood cultures (bacteremia), the Duke criteria, or the modified Duke criteria (infective endocarditis) ; (b) eviThe genotypic designation of the SBSEC was used to report associations between SBSEC and colorectal neoplasia, whenever available.S. gallolyticus subsp gallolyticus antigens in patients with colorectal cancer compared with individuals with no diagnosis of colorectal neoplasia. For cohort studies, we examined the risk of colorectal cancer or adenoma in patients with SBSEC bacteremia (with or without concurrent infective endocarditis) compared with patients without bacteremia.For case–control studies, we examined the odds of intestinal or fecal colonization with SBSEC in patients with colorectal cancer or adenoma, as well as serologic responses against Two reviewers (K.O. and A.G.) independently determined study eligibility by screening titles and abstracts and performing full-text reviews of selected studies. Potential disagreements were resolved by a third reviewer (D.B.). Extractable data included baseline patient characteristics, methods used to diagnose bacteremia or colonization, SBSEC phenotypic and/or genotypic classification, primary and secondary outcomes, and information related to study quality.Two reviewers (K.O. and A.G.) assessed the quality of the included studies using the Newcastle-Ottawa-Scale (NOS) , a tool S. gallolyticus subsp gallolyticus antigens in patients with colorectal cancer compared with individuals with no diagnosis of colorectal neoplasia. We reported odds ratios (ORs) and relative risks (RRs) with 95% confidence intervals. We estimated heterogeneity using the I2 statistic, with I2 values of 25%, 50%, and 75% representing low, moderate, and high heterogeneity, respectively [For data analysis, we used Stata, version 17 . We performed a random-effects meta-analysis using the restricted maximum likelihood method  to estimectively . We set ectively .S. gallolyticus subsp gallolyticus bacteremia compared with individuals without bacteremia, as well as the odds of intestinal or fecal colonization with S. gallolyticus subsp gallolyticus in patients with colorectal cancer compared with controls.We also conducted a subgroup analysis according to the genotypic classification of SBSEC to calculate the risk of colorectal cancer in patients with We found 5033 studies from our literature search in PubMed, EMBASE, and Web of Science. After the removal of duplicates (n = 1291), we examined 3742 studies for eligibility. We excluded 3715 studies based on title and abstract assessment and found 22 studies that met our eligibility criteria  (A).Five cohort studies assessed the risk of underlying colorectal cancer diagnosis in patients with and without SBSEC bacteremia , 53. Spe= 0.00%) A.I2 = 96.65%) (B).In 3 cohort studies included , 49, 53, 96.65%) B.S. gallolyticus subsp gallolyticus bacteremia, respectively, had underlying colorectal cancer. Patients with S. gallolyticus subsp gallolyticus bacteremia were 3.66 times more likely to have a diagnosis of colorectal neoplasia compared with controls   .sodA gene via PCR, 2 studies [sodA probe-based in situ hybridization assay in fecal samples, and 2 studies [I2 = 46.54%) (A). Egger's test showed no evidence of publication bias or small study effects .Isolation of SBSEC bacteria from intestinal or fecal tissue samples was performed in 9 case–control studies , 41–46.  studies , 46 used studies , 42 used 46.54%) A. Egger'S. gallolyticus subsp gallolyticus colonization in intestinal or fecal tissue samples. However, patients with S. gallolyticus subsp gallolyticus colonization were not more likely to have an underlying diagnosis of colorectal cancer compared with controls   .I2 = 0.00%) (B).Moreover, in 4 case–control studies included , 42, 43,= 0.00%) B.S. gallolyticus subsp gallolyticus in patients with colorectal cancer compared with controls [S. gallolyticus subsp gallolyticus cell wall [S. gallolyticus subsp gallolyticus antigens compared with controls   .We repeated the main analysis by including only the high-quality studies (NOS ≥7) to explore the robustness of our findings and ensure that aspects regarding study design and outcome assessment would not interfere with the interpretation of our meta-analysis results. After excluding fair-quality studies, a subgroup analysis was available only for case–control studies estimating the odds of colonization with SBSEC isolates in patients with colorectal neoplasia compared with controls. A sensitivity analysis was not carried out for evaluating the association between SBSEC bacteremia or IgG antibody responses to SBSEC antigens and colorectal neoplasia due to an insufficient number of high-quality studies.I2 = 0.00%) (I2 = 0.00%)  . Next, o= 0.00%) .S. gallolyticus subsp gallolyticus antigens compared with controls. Also, patients with SBSEC bacteremia were 3.73 times more likely to have underlying colorectal cancer compared with controls. Interestingly, our analysis did not find an association between SBSEC bacteremia or colonization and underlying colorectal adenoma diagnosis.In this systematic review and meta-analysis, we explored the association between SBSEC and colorectal neoplasia. We found that patients with colorectal cancer were 2.27 times more likely to be colonized by SBSEC bacteria or have IgG antibody responses to S. gallolyticus subsp gallolyticus invasive infection, was associated with underlying colorectal cancer. Consistent with our findings, a previous meta-analysis, including 3 cohort studies with 140 patients with SBSEC bacteremia and 450 controls, concluded that colorectal cancer risk was almost 8 times higher in patients with SBSEC bacteremia [S. gallolyticus subsp gallolyticus and 151 patients with S. bovis biotype II bacteremia. The authors found that patients with S. gallolyticus subsp gallolyticus bacteremia had a higher risk of colorectal cancer compared with patients with S. bovis biotype II bacteremia. However, our meta-analysis included case–control and cohort studies, and we excluded case reports and case series. Overall, only 1 study [In our analysis, SBSEC bacteremia, and especially cteremia . A meta-cteremia  summariz 1 study  that was 1 study  was incl 1 study  restrictS. gallolyticus subsp gallolyticus antigens were more common in patients with colorectal cancer than controls. However, the presence of such antibodies is not able to indicate acute, localized infection in the colon, and it is unknown whether antibody development for S. gallolyticus subsp gallolyticus antigens occurs only after bacterial entry into the bloodstream or even when the bacterium is still located in the colon [S. gallolyticus subsp gallolyticus in carcinogenesis. Colorectal cancer is the result of a sequence of events leading from normal tissue to adenoma development and then to carcinoma, which can last more than 10 years [Interestingly, we found that IgG antibody responses to he colon . Regardl10 years .S. gallolyticus subsp gallolyticus pili protein antigens for colorectal cancer development and found that serologic responses to S. gallolyticus subsp gallolyticus antigens were 1.36 times more common in patients who developed colorectal cancer, in whom the mean time from blood draw to cancer diagnosis was 3.4 years [S. gallolyticus subsp gallolyticus antigens. Similarly, a large prospective study of 4063 patients with colorectal cancer found that cancer risk was associated with IgG antibody detection against S. gallolyticus subsp gallolyticus pilus proteins within 10 years of blood draw, but not beyond 10 years of antibody positivity. Individuals diagnosed within 10 years of blood draw were also more likely to have precursor lesions in their colon [S. gallolyticus subsp gallolyticus antigens can be used as a marker of underlying colorectal neoplasia.From the studies included in our analysis, Butt et al. prospectively assessed patients with and without IgG antibodies against .4 years . The latir colon . Taken tOur results showed that patients with colorectal cancer, but not colorectal adenoma, were more likely to be colonized by SBSEC isolates compared with controls. Contrary to our findings, a previous meta-analysis assessing 515 patients with colorectal neoplasia (either adenoma or carcinoma) and 642 controls found that culture of SBSEC isolates from fecal specimens did not occur with greater frequency in patients with colorectal neoplasia compared with controls . Also, BS. gallolyticus subsp gallolyticus was not associated with underlying colorectal cancer diagnosis. Out of all members of the SBSEC, S. gallolyticus subsp gallolyticus has been described to adhere to malignant colorectal tissue with higher affinity than other SBSEC bacteria due to the unique property of its pili proteins binding exposed collagen fibers emerging from the basal lamina of malignant tissue [S. gallolyticus subsp gallolyticus promotes tumorigenesis by modifying the ability of intestinal and cancerous cells to detoxify dietary components, thus allowing for DNA damage to accumulate, eventually increasing cancer risk [S. gallolyticus subsp gallolyticus enhanced cellular proliferation by upregulating beta-catenin, a pivotal molecule in colon tumorigenesis [gallolyticus subsp gallolyticus degraded tannic acid, which is a substance known to have cytotoxic effects against colorectal cancer cells [S. gallolyticus subsp gallolyticus colonization and colorectal cancer can be explained by the small sample size used in our subgroup analysis or the involvement of other SBSEC bacteria in colorectal cancer development. Associations between SBSEC bacteria other than S. gallolyticus subsp gallolyticus and colorectal neoplasia stem from case reports and case series [S. gallolyticus subsp gallolyticus may preferentially colonize colorectal tissue [Interestingly, our subgroup analysis found that colonization with t tissue , 58, 59.t tissue  found thcer risk , 62. Kumcer risk  also demigenesis , while Oigenesis  found ther cells . Failuree series , 17, 51.S. gallolyticus subsp gallolyticus, so comparison of the different subspecies with regards to risk of colorectal neoplasia was not possible. Next, colonization with SBSEC isolates was assessed via fecal culture evaluation in 7 studies [S. gallolyticus subsp gallolyticus antigens, and we could not perform separate analyses for specific antigenic targets due to insufficient data.Regarding the limitations of our analysis, only 2 studies reported underlying patient comorbidities , 54 and  studies , 43–46,  studies , 42 examS. gallolyticus subsp gallolyticus antigens with underlying colorectal neoplasia. Strengthening of these observations is necessary as SBSEC detection in the blood or isolation from fecal or colonic tissue can be used as a marker of underlying malignancy. Although evidence about the role of SBSEC in colorectal adenoma development is available in experimental and observational studies [S. gallolyticus subsp gallolyticus antigens can also provide us with immunological markers for early detection of colorectal cancer.In conclusion, our analysis reinforces results from previous studies that link SBSEC infection or colonization with enhanced colorectal cancer risk and associate serologic responses to  studies , 49, 53,ofad547_Supplementary_DataClick here for additional data file.


Given the potentially negative effects of hearing loss on mental health and cognitive function, it is critical to gain a better understanding of the mechanisms underlying the link between hearing loss and cognitive impairment. This study aimed to investigate the moderating effects of social relationships, including their components in the role of depressive symptoms as a mediator between hearing loss and cognitive impairment.Cross-sectional analyses were conducted with 8,094 Chinese older adults (aged ≥65 years) from the Chinese Longitudinal Healthy Longevity Survey in 2018. Simple mediation analysis and moderated mediation analysis were conducted to examine the roles of depressive symptoms and social relationships in the association between hearing loss and cognitive impairment.B = 0.021; 95% CI: ], and path c’ (hearing loss-cognitive function) . Furthermore, social activities and social networks moderated both the direct and indirect effects of moderated mediation. However, there appeared to be no moderated effect of social support for both the direct and indirect paths.There is a significant correlation between hearing loss, depressive symptoms, social relationships, and cognitive function. Depressive symptoms partially mediated the association between hearing loss and cognitive function . Social relationships moderated the effect of hearing loss on cognitive function through both path b (depressive symptoms - cognitive function) [Social relationships moderated both the direct and indirect effects of depressive symptoms on the association between hearing loss and cognitive impairment. These findings shed light on the mechanisms underlying the relationship between hearing loss and cognitive impairment in Chinese older adults. It might be worthwhile to recommend multidimensional health and social interventions aimed at improving mental health and social inclusion among older adults with hearing loss. About two-thirds of American adults over the age of 70 suffer from hearing loss, but less than 20% of them receive treatment  . In ChinWith global aging, the prevalence of dementia is expected to double every 20 years, and the number of dementia patients worldwide is estimated to soar from 57.4 million in 2019 to 152.8 million in 2050 . AccordiDepression is common in older adults. Concerningly, one in five older persons with hearing loss report clinically significant depressive symptoms that necessitate treatment, and hearing loss is also connected to the gradual introduction of new depressed symptoms over time . Hearingvia different domains have been conducted. In the context of the above theory, interindividual variability in social activity, social networks, and social support may produce different outcomes. Correspondingly, we included all three critical dimensions of social relationships in our analyses.Additionally, behavioral explanations for the potential causal relationship discussed above have been put forth. These include social exclusion, loneliness, decreased mobility, and difficulties in everyday tasks, all of which raise the likelihood of cognitive impairment . Social Overall, it is uncommon for research to be undertaken where both psychological and social pathways are addressed at the same time to comprehend how hearing loss affects cognition. Therefore, the first aim of this study was to determine whether depressive symptoms have a mediating effect on the relationship between hearing loss and cognitive impairment. Another aim of this study was to determine whether social relationships, including their components, have any moderating effect on the direct and indirect correlations between hearing loss and cognitive impairment . SpecifiH1: Depressive symptoms would act as a mediator between hearing loss and cognitive impairment.H2: The direct and indirect correlations between hearing loss and cognitive impairment would be moderated by social relationships, with depressive symptoms acting as a mediator.H3: The direct and indirect correlations between hearing loss and cognitive impairment would be moderated by social activities, social networks, and social support, with depressive symptoms acting as a mediator.2.2.1.n = 95) were excluded from the current analysis. And we restricted our final analysis to 8,094 older adults with completed information on the questions we are concerned about. Details of the screening procedure are described in We conducted a cross-sectional analysis of the dataset derived from the eighth wave of the Chinese Longitudinal Healthy Longevity Survey (CLHLS) in 2018, a national representative prospective cohort study of Chinese adults aged 65 and older in major provinces (23 out of 31 provinces) in China. Details of the study participants and methods have been reported elsewhere . In the Participants with no Mini-Mental State Examination (MMSE) scores, data on frailty, depression, or missing data on social ties were eliminated. If any of the sample’s important variables have missing values, they will be eliminated as well. This analysis comprised 7,525 individuals’ data.Based on prior research , 18, 19 2.2.2.2.1.Based on prior research, the Chinese adaptation of the modified Mini-Mental State Examination (MMSE) was utilized in this study to assess cognitive function , 20. The2.3.2.3.1.To assess the participants’ self-perceived hearing status, the following question was asked (without hearing aids): “Do you feel you have hearing difficulty?” The response options were “Yes” (coded as having hearing loss)/“No” (signified not having hearing loss) , 26. Sel2.4.2.4.1.The 10-item Center for Epidemiologic Studies Depression (CES-D-10) was used to assess depressive symptoms, which was a self-reported scale for assessing the symptoms of depression in the past week . The CES2.5.2.5.1.According to previous studies , 29, socIn the context of Berkman et al.’s framework , playing2.6.As covariates, sociodemographic characteristics, lifestyles, and health status were classified as potentially related factors in previous studies .2.6.1.The sociodemographic characteristics contained age (in years), gender , education , residence , and financial support .2.6.2.According to a recent study , a combi2.6.3.In this study, health status mainly involves the ability of daily living (ADL) and chronic diseases. The ADL scale was used to evaluate functional ability, which includes six domains: bathing, dressing, eating, toileting, continence, and indoor transfer. Scores were assigned based on the independence of individuals in completing each of the above actions: 1 = complete dependency, 2 = partial independence, and 3 = complete independence. After adding six items, the ADL score ranged from 6 to 18. Responses with higher scores indicated greater independence and functional ability. Cronbach’s α coefficient of the ADL for this study was 0.86. Detailed variable codes are presented in 2.7.p-value less than 0.05 (two-sided tests).Summary statistics were reported as the means and standard deviation for numerical variables and as the frequency for categorical variables. Chi-square tests were employed to examine proportional differences, while t-tests were performed to compute mean differences. Pearson correlation analysis was performed to explore the linear relationships between all the variables. PROCESS SPSS macro  was employed to examine the moderated mediation model . In Haye3.3.1.p < 0.001). Meanwhile, participants with cognitive impairment were more likely to have hearing loss, depressive symptoms, and poorer social relationships  (p < 0.001). Neither group had significant differences in ADL scores (p > 0.05).We examine the sample characteristics stratified by the cognitive state in 3.2.p < 0.001).As shown in 3.3.B = −4.620, 95% CI: ]. Model 2 explored the relationship between hearing loss and cognitive function when adjusting for sociodemographic characteristics, lifestyles, and health status. Hearing loss was significantly associated with cognitive function . Age , gender , financial support , and ADL  were negatively associated with cognitive function. Education  and total lifestyle score  were positively associated with cognitive function. The significance and direction of the correlation coefficients between hearing loss and cognitive function did not change from Model 1 to Model 2, indicating that hearing loss is a significant predictor of cognitive function.As shown in 4.B = 0.745, 95% CI: ] in a simple mediation model (Model 4), as shown in B = −0.153, 95% CI: ]. Hearing loss was also associated with cognitive function . Furthermore, we found that hearing loss was associated with depressive symptoms, which had a significant indirect effect on cognitive function , accounting for 5.07% of the total effect.To further elucidate the mechanisms underlying the association between hearing loss and cognitive function, we examined the mediating role of depressive symptoms. Hearing loss and depressive symptoms were positively correlated [4.1.B = −0.056, p = 0.339). However, for cognitive function, an interaction effect was observed between depressive symptoms and social relationships , as well as between hearing loss and social relationships . Therefore, the hypothesized model has been modified by removing social relationships as a moderating factor on path a , b , and c’ , social activity moderated the impact of hearing loss on cognitive function. While through both path a  and path c’ , social networks moderated the impact of hearing loss on cognitive function. Moreover, the direct and indirect effects of hearing loss on cognition were tested using Model 59, but neither direct nor indirect paths appeared to be moderated by social support  or above  one standard deviation, participants with hearing loss had lower cognitive function than participants with normal hearing  or above  one standard deviation , the results of our study showed that exposure to hearing loss increased the risk of depressive symptoms among older adults. Hearing loss is associated with depressive symptoms in older adults linked to changes in psychosocial experiences and declines in cortical activity , 47, 48.symptoms . Second,symptoms . In addisymptoms . Meanwhi5.2.Social relationships negatively correlated with depressive symptoms, as expected. The odds of developing depressive symptoms are lower for older adults who have more social relationships. In line with previous empirical studies  and the In line with previous findings that strong social relationships buffers depression  and probFurthermore, hearing loss and cognitive impairment were also moderated by social relationships. Specifically, hearing-impaired older adults with low social relationships exhibited lower cognitive function than those with high social relationships. This result is consistent with previous studies and extends them by demonstrating the buffering effect of social relationships and its specific component in the association between hearing loss and cognitive decline among older adults , 63. TheSome limitations should be addressed in this study. Firstly, the cross-sectional design renders causal inferences about the association between hearing loss, depressive symptoms, and cognitive impairment difficult. The causal direction between hearing loss and cognitive impairment and more accurate mediation estimates could be explored in the future with a longitudinal design. Secondly, self-report measures can be prone to bias and distortion. It is therefore essential to use multiple measures such as an in-depth interview or observation of behavior. Thirdly, since lacked relevant details, the frequency, severity, and duration of hearing loss as well as the information on hearing aids were not considered in this study. Future research should verify whether these factors might be involved in the moderated-mediation model among older adults.Despite the above limitations, there are theoretical and practical implications to our findings. Based on theoretical considerations, the present findings provide an empirical framework for testing depressive symptoms’ mediating role in the association of hearing loss with cognitive impairment, as well as social relationships’ moderating role. As a consequence of this framework, we may better understand how hearing loss is related to cognitive impairment among Chinese older adults. Around the world, we must shift the way we look at the hearing, hearing loss, and how hearing rehabilitation impacts the overall quality of life of older adults. From a practical view, because hearing loss increases the likelihood of depressive symptoms among older adults, families, caregivers, healthcare personnel, and institutions should pay more attention to older adults with hearing loss. In rehabilitative practice, broader consultations should especially involve discussing emotional elements of social interaction with patients and how hearing loss affects cognitive and physical functioning. Meanwhile, the identification of vulnerable individuals is essential to ensuring that prevention and early intervention programs are targeted at them. This moderating mediation model has the potential to facilitate earlier identification, enhance motivation for hearing aid and treatment, as well as reduce stigma. Overall, this could be beneficial for older adults with hearing loss, their families and social circles, the healthcare system, and society as a whole.6.As a whole, we found that depressive symptoms played a partial mediating role in the association between hearing loss and cognitive impairment among a nationally representative sample of Chinese older adults. Furthermore, in addition to social relationships, these two components, i.e., social activity and social network, moderated the association between hearing loss and cognitive impairment. It might be worthwhile to recommend multidimensional health and social interventions aimed at improving mental health and social inclusion among older adults with hearing loss.https://opendata.pku.edu.cn/dataverse/CHADS.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number (s) can be found below: The research has been reviewed and approved by the Research Ethics Committee of Peking University . The patients/participants provided their written informed consent to participate in this study.XC and JZ conceived the concept and design of the study. XC and QL contributed to data cleaning and analysis. JL and BY contributed to the writing assistance and proofreading of the article. All authors approved the final version of the manuscript.This study was supported in part by a grant from STI2030-Major Projects (2021ZD0200700), the National Natural Science Foundation of China , the Natural Science Foundation of Hunan (2021JJ30037), the Health Commission of Hunan Province , and the Hunan Medical Association (HNA202101008).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.


Noise-induced hearing loss is a type of sensorineural hearing loss caused by longterm exposure to loud noise. This study provides insight into hearing loss problems the general population faces. The study aimed to find out the prevalence of noise-induced hearing loss among patients needing pure tone audiometry evaluation in a tertiary care centre.A descriptive cross-sectional study was conducted from 1 January 2021 to 30 July 2021 among patients requiring pure tone audiometry evaluation in the outpatient Department of Otorhinolaryngology in a tertiary care centre. The study was conducted after ethical approval from Institutional Review Committee (Reference number: 2812202001). Pure tone audiometry was used to diagnose noise-induced hearing loss. Convenience sampling was done. Point estimate and 95% Confidence Interval were calculated.Out of 690 patients, 14 (2.02%)  were diagnosed with noise-induced hearing loss.The prevalence of noise-induced hearing loss among patients requiring pure tone audiometry evaluation was similar to other studies conducted in similar settings. In the long run, NIHL increases morbidity and lowers the quality of life of those affected.Noise-induced hearing loss (NIHL) is a sensory neural type of hearing loss where chronic exposure to less intense sound damages cochlear hair cells and nerves.2 Henceforth, understanding the prevalence of noise-induced hearing loss in our hospital scenario is imperative in providing medical professionals with the information to tackle these cases better.NIHL is one of the most common preventable causes of sensorineural hearing loss.This study aimed to find out the prevalence of NIHL among patients requiring pure tone audiometry (PTA) evaluation in a tertiary care centre.A descriptive cross-sectional study was conducted in the Department of Otorhinolaryngology of Kathmandu Medical College and Teaching Hospital, Kathmandu, Nepal among patients requiring PTA evaluation from 1 January 2021 to 30 July 2021. All the audiogram reports of the patients reported at this time frame were evaluated for evidence of NIHL. Ethical approval was obtained from the Institutional Review Committee (Reference number: 2812202001). The audiometry was performed by a technologist trained in audiometric techniques. All ages of patients who underwent audiometrie assessment during the study period were included in the study. Convenience sampling was used.Where,Z= 1.96 at 95% Confidence Interval (CI)3p = prevalence of noise-induced hearing loss taken from previous study as 1.82%q = 1-pe = error of margin, 1%The calculated sample size was 687. However, 690 samples were included in the study.5 This method for diagnosis is widely used by different authors in kinds of literature and in clinical practice. While 4 kHz is the classic frequency affected, the notch can be noted elsewhere because of the noise frequency range in which cochlear damage occurs.6 Audiometric dip seen only on 4 kHz is thus referred to as a narrow dip (V type) otherwise it is said to be a wide dip (U type).7 As per study criteria, audiograms having simultaneous conductive hearing loss i.e. Air-Bone gap >10 dB were excluded for NIHL prevalence. The severity of NIHL was graded according to WHO standards after taking the average of the 4 frequencies i.e. 500 Hz, 1000 Hz, 2000 Hz, and 4000 Hz in the right and left ears separately.9 Patients with the NIHL result in even one ear were considered for diagnosis and included in prevalence.The diagnosis for noise-induced hearing loss is based on finding an audiometric notch between 3 kHz to 6 kHz, alongside a history of noise exposure and symptoms of muffled hearing loss, vertigo, and tinnitus.Data were entered in Microsoft Excel 2016 and analyzed using IBM SPSS Statistics version 22.0. Point estimate and 95% CI were calculated.Among 690 participants, the prevalence of NIHL was 14 (2.02%) . The mean age of NIHL-affected individuals was 36.36±10.20 years. A total of 7 (50%) complained only of muffled hearing loss, 5 (35.71%) had muffled hearing loss with tinnitus, 1 (7.14%) had tinnitus while only 1 (7.14%) had all of these complaints. There were 5 (64.28%) females and 9 (35.71%) males. Most of the patients had both ears affected and only a few had unilateral NIHL. There were about 11 (78.57%) cases of binaural noise-induced hearing loss and 3 (21.40%) cases of unilateral hearing loss. In terms of unilateral involvement, 2 (14.28%) and 1 (7.14%) were seen only in the left and right ears, respectively.The severity of the hearing loss is graded according to WHO standards. A total of 6 (42.85%) and 8 (57.14%) cases were in the mild range of hearing loss in the left and right ears respectively .In the left ear 5 (35.71%) had a narrow dip and 7 (50%) had a wide dip .In the right ear, 6 (42.85%) had a narrow dip and 7 (50%) had a wide dip. Additionally, most of the narrow and wide dips of 4 kHz i.e. 12 (85.71%) cases had depths in between 26 to 50 dB .On the left ear, there were 6 (42.85%) cases of mild hearing loss, in which 3 (21.42%) had narrow and 3 (21.42%) others had wide shaped notches at 4 kHz .There were 8 (57.14 %) cases of mild hearing loss in the right ears, but a decrease to 4 kHz beyond 25 dB was observed in 13 (92.85 %) cases .3 Looking at an occupational noise-induced hearing loss, where prevalence is calculated among high-risk populations, the prevalence is found to be substantially higher, ranging from 26.80-66.4%.12In our study, the prevalence of NIHL was found to be 2.02% out of 690 patients. In a study done in a tertiary care hospital in Jharkhand, its prevalence in an Outpatient Department setting was similar to our study at 1.83%.13 Meanwhile, in a study of medical students in Pakistan, women were three times more affected by high-frequency sounds indicating NIHL.14 Our patients presented with chief complaints of muffled hearing, tinnitus, and vertigo. 13 (92.85%) experienced hearing loss. In a study conducted in a hospital setting in Northern India, 54% complained solely of hearing loss, while the other half complained of tinnitus and hearing loss.15 In the same study, NIHL binaural involvement was observed in 74%, which is similar to our study, 78.57%. In a police survey, only 61.64% had a binaural association, which is lower than our study.12 The symmetrical binaural mild to moderate hearing loss in NIHL is something that traditional education educates us about. However, a sizable proportion of patients have asymmetrical thresholds.Similarly, the ratio of males to females affected with NIHL was around 1.8:1. A study from China also indicates significant sex differences where males are at 2.49 times the higher risk than females.16 In a study of Pokhara woodworkers, 30.68% of carpenters were affected, with 14% having mild hearing loss, 14% having moderate hearing loss, and the remaining 3% having severe hearing loss.11 In the same research, 44% of sawyers were affected, with 11% having mild hearing loss, 28% having moderate hearing loss, and 5% having severe hearing loss.In our study, roughly half of the cases, 42.90% in the left ear and 57.10% in the right ear had mild hearing loss, while the rest were normal. It is interesting to note that there were only 8 (57.14%) cases of mild hearing loss in the right ears, but a decrease to 4 kHz beyond 25 dB was observed in 13 (92.85%) cases. This suggests that there were more narrow troughs at 4 kHz, averaging close to a lower range of hearing loss. In a separate study of police officers, it was discovered that 93% of them had mild NIHL, 3.5% had moderate NIHL, and 3.5% had severe NIHL.5In our study, most cases- 71.42% in left ears and 85.71 % in right ears had a depth of 26-50 dB at 4 kHz with as many narrow as wide notch in both ears. A study reported that 28% of the narrow notches and 21% of the wide notches were between 16 and 30 dB, which is lower than our study's findings.The limitations of this study could be the sample size bias. This single-centre study of patients in various professions cannot be generalized to highrisk occupational groups or the general population. Furthermore, since this is a descriptive study, we were unable to find associations between the variables and disease processes.This study found that the prevalence of NIHL amongst patients requiring PTA evaluation was similar to other studies conducted in similar settings. Although most patients had a hearing degree at a normal range according to WHO standards, the NIHL problem still exists as indicated by the narrow audiometric notch at 4 kHz dip. Given that this is the most prevalent preventable cause of hearing loss, appropriate actions should be taken timely to avoid it.


N = 24, 16 females) during tRNS delivery separately over V1 and over the retina, determined the optimal tRNS intensities for each individual (ind-tRNS), and retested the effects of ind-tRNS within the sessions. We further investigated whether we could reproduce the ind-tRNS-induced modulation on a different session . Finally, we tested whether the simultaneous application of ind-tRNS to the retina and V1 causes additive effects. Moreover, we present detailed simulations of the induced electric field across the visual system. We found that at the group level tRNS decreases VCT compared with baseline when delivered to the V1. Beneficial effects of ind-tRNS could be replicated when retested within the same experimental session but not when retested in a separate session. Applying tRNS to the retina did not cause a systematic reduction of VCT, regardless of whether the individually optimized intensity was considered or not. We also did not observe consistent additive effects of V1 and retina stimulation. Our findings demonstrate significant tRNS-induced modulation of visual contrast processing in V1 but not in the retina.Transcranial random noise stimulation (tRNS) has been shown to significantly improve visual perception. Previous studies demonstrated that tRNS delivered over cortical areas acutely enhances visual contrast detection of weak stimuli. However, it is currently unknown whether tRNS-induced signal enhancement could be achieved within different neural substrates along the retino-cortical pathway. In three experimental sessions, we tested whether tRNS applied to the primary visual cortex (V1) and/or to the retina improves visual contrast detection. We first measured visual contrast detection threshold (VCT;  Our findings confirm previous evidence showing acute online benefits of transcranial random noise stimulation (tRNS) of primary visual cortex (V1) on visual contrast detection in accordance with the stochastic resonance (SR) phenomenon. We further extend it, demonstrating that the optimal tRNS intensity varies among participants, but when individually tailored it can improve visual processing when re-tested within the experimental session. The tRNS-induced enhancement in visual sensitivity was observed for cortical contrast processing, but stimulation of the retina did not lead to systematic effects.Transcranial random noise stimulation (tRNS) has been shown to significantly improve visual perception  or both on visual detection performance.https://osf.io/gacjw). The only difference to preregistered original plan concerns the included sample population. We stated that only participants who completed all three sessions will be included in our study. During data collection not all the individuals who completed the first and second sessions participated in the third session, because of the COVID-19 pandemic (N = 24) despite dropouts and lower sample size in session 3 .This study was preregistered on the Open Science Framework platform ANOVA (four levels of stimulation condition), α = 0.05, and 90% power, assuming the correlations among repeated measures = 0.5. However, there was no prior data available to investigate whether applying tRNS to two separate neural structures can cause additive effects. Therefore, we include more participants to ensure sufficient power. Moreover, this estimation hinges on the assumption that approx. 80% of the participants exhibit a behavioral response to tRNS . We also excluded individuals with exceptional contrast threshold modulation in tRNS trials with respect to no tRNS trials (>100%) to avoid accidental results, e.g., because of participants responding without paying attention to the task. From the initially recruited sample of 32 participants, we excluded eight individuals . The final sample consisted of 24 healthy volunteers  with normal or corrected-to-normal vision , during visual task performance see A. In eacThe order of experimental sessions for V1 and retina stimulation were counterbalanced across participants (13 participants started with V1 and 11 with retina stimulation). These experimental sessions took place on different days which were on average two weeks apart. Because of COVID-19 restrictions, the third session had to be delayed by five months on average.V1) and the retina session (ind-tRNSretina). In the third session we then applied ind-tRNSV1 and ind-tRNSretina to investigate the effect on VCT when V1 and retina are stimulated simultaneously.Our main outcome parameter in all experimental sessions was a threshold of visual contrast detection (VCT) that was determined for each of the different tRNS conditions. VCT was independently estimated twice, in two separate blocks within each session see B. During2 . The target visual stimuli were presented on a uniform gray background in the form of a Gabor patch, a pattern of sinusoidal luminance grating displayed within a Gaussian envelope  using a function in the Psychtoolbox extension that defines the stimulus intensity with Michelson contrast  and dispIn all three experiments participants performed a four-alternative forced choice (4-AFC) visual task, designed to assess an individual VCT, separately for each tRNS condition. A 4-AFC protocol was shown to be more efficient for threshold estimation than commonly used 2-AFC . ParticiDuring the main experiment, VCT was estimated using the QUEST staircase maximum likelihood procedure  implemenIn tRNS trials, high-frequency tRNS  with no offset was delivered. The probability function of random current intensities followed a Gaussian distribution with 99% of the values lying between the peak-to-peak amplitude . StimulaV1, ind-tRNSretina, ind-tRNSV1+retina in V1+Retina session) or no tRNS. Their task after each trial was to indicate on a keyboard whether they felt a sensation underneath the tRNS electrodes. The determined detection accuracy  of the cutaneous sensation induced by tRNS served as a control to estimate whether transcutaneous effects of the stimulation might have confounded the experimental outcomes  and used the mean HR as a covariate .Since we used a very brief stimulation time (2 s only), fade in/out periods were not possible . Accordioutcomes . In the In the V1 session, we asked whether tRNS over V1 modulates VCT. To target V1 we used an electrode montage that was previously shown to be suitable for V1 stimulation . One tRN2 in the 0.75, 1, and 1.5 mA condition, respectively (tRNS was delivered with 0.75 mA (low), 1 mA (medium), and 1.5 mA (high) amplitude (peak-to-baseline), resulting in maximum current density of 60 mulation . tRNS poectively .To further explore the influence of electrical random noise on visual processing we delivered tRNS over the retina during a visual contrast detection task. To stimulate the retina, face skin-friendly self-adhesive round electrodes with a diameter of 32 mm (TENS-EMS pads Axion GmbH) were placed on the sphenoid bones of the right and left temples (F9 and F10 in the 10–20 EEG system). Electroconductive gel was applied to the contact side of each electrode to additionally reduce skin impedance.2 in the 0.1-, 0.2-, and 0.3-mA condition, respectively (N = 30) to assess a flickering threshold when low-frequency tRNS was used (0.1–100 Hz). We found that flickering was perceived for a mean intensity of 0.146 ± 0.08 mA (peak-to-baseline) suggesting that the stimulation intensities chosen in this experiment should be suitable to reach and effectively stimulate the retina. Interestingly, perceived flickering during low-frequency tRNS suggests a suprathreshold influence of the stimulation, in contrast to stimulation levels usually induced in the brain using tES, i.e., potentially more effective. Note also, that the sphenoid bones are much thinner than the back of the skull. Our pilot experiment further revealed that flickering was induced by low-frequency tRNS but not by high-frequency tRNS (as used in the main experiments), thus the visual task remained unaffected by flickering sensation during hf-tRNS sessions. Finally, we designed our stimulation conditions considering the feasibility of delivering tES to the face of the participants. The skin around the eyes is quite sensitive for most of the people and increasing the intensity for retinal stimulation could be painful for the participants. Based on feedback provided by the pilot participants we found that higher intensities (above the ones used here) resulted in discomfort induced by tES applied to the temples. Importantly, the discomfort because of tES could then additionally influence the task performance.Dose–response effects were assessed with VCT during tRNS applied with the intensity of 0.1-mA (low), 0.2-mA (medium), and 0.3-mA (high) amplitude (peak-to-baseline), resulting in a maximum current density of 29.3 mulation . tRNS poectively . The choectively . FurtherThe final experimental session aimed to investigate potential additive effects of delivering electrical random noise simultaneously to V1 and the retina on visual contrast sensitivity.V1 and ind-tRNSretina, corresponding to the intensity causing the lowest VCT, i.e., biggest improvement in contrast sensitivity during V1 and retina sessions; see above, General study design).In this session, we combined the electrodes montages over V1 and the retina and applied tRNS with individual optimal intensities as determined in the first two experimental sessions (ind-tRNSV1), (2) tRNS over retina at its optimal intensity (ind-tRNSretina), (3) simultaneous tRNS over V1 and the retina at their respective optimal intensities (ind-tRNSV1+retina), and (4) no tRNS. All conditions were interleaved and presented in a randomized order.In the V1+Retina session, we compared the VCT in four conditions: (1) tRNS over V1 at its optimal intensity , and V1.https://github.com/vabelyaeva/modeling_visual_system.To assess the exposure related to the stimulation over the visual system under different electrode configurations, a computational model, which replicated the intervention, was created using Sim4Life (ZMT Zurich Med Tech AG) platform for computational life-sciences investigations. To execute the electromagnetic (EM) simulations, we selected the detailed anatomic head model A, i.e., To replicate the experimental setup, we generated four electrodes that were positioned on the skin of the MIDA model in accordance with the EEG 10–20 system A. The fiThe EM simulations were performed using Sim4Life’s rectilinear version of the “Electro Ohmic Quasi-Static” finite element method (FEM) solver, which is suitable because the length-scales are much smaller than the wavelength and ohmic currents dominate over displacement currents. The simulations were run primarily to estimate spatial distribution of the effectively stimulated area, as the software is designed to simulate the induced E-field for the direct current only, without considering the temporal characteristics of tRNS. The model geometry encompassed the head and neck of the MIDA and was discretized using a grid with a resolution of 0.5–0.75 mm, a resolution found to be sufficient for the investigation-of-interest in a grid convergence analysis. The refinement was the finest near the electrodes. To account for the considerable thinness of the retina, a separate convergence analysis was conducted, which concluded that a refinement of 0.3 mm is needed to ensure accurate total field estimations in the retina. Following the construction of the final grid, which contained >109 MCells, two EM simulations were executed for each electrode pair, by assigning Dirichlet (voltage) boundary conditions of +1 V to the Oz electrode  and −1 V to Cz . After computing the EM simulations, the resulting E-fields were normalized to the minimum, medium and maximum amplitude of the experimentally applied current intensities: 0.75, 1, and 1.5 mA for V1 stimulation (Oz and Cz pair) and 0.1, 0.2, and 0.3 mA for retina stimulation (F9 and F10 pair).All the statistical analyses were preregistered and did not deviate from the original plan. Statistical analyses were performed in IBM SPSS Statistics version 26.0 (IBM Corp.). All data were tested for normal distribution using the Shapiro–Wilks test. Variance is reported as SD in the main text and as SE in the figures.time  using the Bayes factor testing for evaluation the absence versus presence of an effect.First, we tested whether baseline VCT in the no tRNS condition differed across the three experimental sessions using a Bayesian rmANOVA with the factor post hoc tests; preplanned comparisons of stimulation with low, medium, and high tRNS intensity vs no tRNS baseline). Partial η2  was analyzed with a rmANOVA with the factor tRNS  and the factor block . For each individual and each block, we determined the maximal behavioral improvement, i.e., lowest VCT measured when tRNS was applied, and the associated “optimal” tRNS intensity (ind-tRNSV1). The maximal behavioral improvements in the first and the second block were compared using a t test (two-tailed) for dependent measurements. We further tested whether ind-tRNSV1 intensities of the first and second block were correlated using Spearman’s rank correlation coefficient . Importantly, we determined ind-tRNSV1 in the first block, and then used the VCT data of the separate second block to test whether the associated VCT is lower compared with the no tRNS condition using t tests for dependent measures. Since we had the directional hypothesis that VCT is lower for the optimal tRNS intensity compared with no tRNS this test was one-tailed. Determining ind-tRNSV1 and testing its effect on VCT in two separate datasets is important to not overestimate the effect of tRNS on visual detection behavior (VCT data collected in the V1 session (tRNSbehavior .retina) was analyzed with a rmANOVA with the factor of tRNS  and the factor block . Again, for each individual and each block, we determined the maximal behavioral improvement and the associated ind-tRNSretina. We compared results obtained in the first and second block using the same statistical tests as for the V1 session. The maximal behavioral improvements were compared using a t test (two-tailed) for dependent measurements. Correlation of ind-tRNSretina intensity of the first and second block was tested using Spearman’s rank correlation coefficient. We examined whether the ind-tRNSretina determined based on the best behavioral performance in first block, caused VCT to be lower compared with the no tRNS condition when retested on the independent dataset (second block) using t tests (one-tailed) for dependent measures.VCT data collected in the Retina session (tRNSV1+retina) was analyzed with a rmANOVA with the factor tRNS site  and the factor block . Moreover, we compared behavioral improvement for ind-tRNSV1 and ind-tRNSretina between sessions  using a Pearson correlation coefficient.VCT data collected in the V1+Retina session  with adding cutaneous sensation as covariate .time (1–6) revealed that the baseline VCT measured in the no tRNS condition did not differ over time  indicating that detection performance was rather stable across sessions.We first tested whether VCT measured during the no tRNS condition differed between the experimental sessions or blocks  = 4.54, p = 0.006, Post hoc comparisons revealed that the 0.75 mA stimulation was most effective in boosting contrast processing, which differed significantly from the no tRNS control condition . There was also a trend toward significantly lower VCT during 1 mA stimulation . Neither the main effect of block  = 0.18, p = 0.678) nor tRNS*block interaction  = 0.82, p = 0.488) reached significance.In the V1 session, we investigated whether tRNS modulates the visual contrast detection when applied to V1. We measured VCT during tRNSsitivity A. Post hV1 conditions . We reanalyzed our main outcome parameter by adding sensation detection HR as a covariate. The main effect of tRNS remained highly significant  = 4.17, p = 0.009, The control measurement of cutaneous sensation revealed that most of our participants could detect tRNSV1-induced lowering of the VCT relative to the no tRNS condition) did not differ between the first (MD = −17.98 ± 19.6%) and the second block  = −0.304, p = 0.764). However, participants’ optimal ind-tRNSV1 intensity of block 1 and 2  were not correlated . This suggests that participants may have profited to a different extend from variable intensities between the blocks.When comparing tRNS-induced effects between the first and second block we found that the maximal behavioral improvement . Accordingly, V1 relative to the no tRNS baseline in 15 out of 24 individuals (MD = −4.45 ± 17.9%) and this effect reached statistical significance (t(23) = 1.72, p = 0.049, d = 0.2; V1 intensity and the associated VCT effect were determined on independent datasets to avoid circularity.Finally, we determined ind-tRNSst block B and tesretina at intensities of 0.1, 0.2, to 0.3 mA versus no tRNS control condition. Although, on the group level, we observed decrease in VCT with increasing tRNSretina intensity (MD = −6.93 ± 17.39% on average in the first and second block for 0.3 mA) the effect was not significant  = 1.69, p = 0.177; block  = 0.04, p = 0.840) or tRNS*block interaction  = 0.55, p = 0.652). The maximal behavioral improvements, defined as the maximal tRNSretina-induced lowering of the VCT were not significantly different between the first (MD = −19.44 ± 19.43%) and the second (MD = −11.96 ± 22.79%) block (t(23) = −1.197, p = 0.243). The optimal ind-tRNSretina intensity defined in the first and second block were not significantly correlated among participants , indicating that variable intensities between the blocks did not consistently affect processing in the retina. The ind-tRNSretina determined in the first block (t(23) = 1.05, p = 0.15, VCT decrease in 13 out of 24 individuals, MD = −1.89 ± 25.29%; In the Retina session, we explored the effects of tRNS applied over the retina on visual contrast detection. VCT was measured during tRNSV1 session, the control measurement of cutaneous sensation revealed that the participants could detect tRNSretina conditions . As we did not observe a significant effect of tRNSretina, here we did not run an additional control analysis.Similarly to the tRNSV1 and ind-tRNSretina determined in sessions 1 and 2 would have additive effects when combined during simultaneous V1 and retina stimulation  = 0.54, p = 0.660), block  = 2.73, p = 0.116) nor tRNS site*block interaction  = 0.31, p = 0.822). Although the simultaneous stimulation with ind-tRNSV1+retina led to a decrease in VCT in the first block (MD = −4.12 ± 25.64%), this difference was not significant (t(18) = 0.83, p = 0.21; The aim of V1+Retina session was to explore whether the effects of ind-tRNSmulation A. AgainsV1 = 56.58 ± 43.97%, ind-tRNSretina = 19.74 ± 31.82%, ind-tRNSV1+retina = 67.11 ± 39.13%, mean HR = 47.81 ± 28.03%). As we did not observe a significant effect of the stimulation, we did not run an additional control analysis.The control measurement of cutaneous sensation in the third session revealed that the participants could detect tRNS conditions (HR at ind-tRNSV1 found in V1 session was not reproduced between sessions when VCT was measured during ind-tRNSV1 in session 3 (t(18) = −0.18, p = 0.43, MD = 2.24 ± 23.63%, and t(18) = −1.37, p = 0.09, MD = 4.1 ± 14.28%; V1 in the first blocks of V1 and V1+Retina sessions , indicating that once-optimized tRNS intensity does not lead to consistent effects between sessions. Similarly to Retina session, participants’ ind-tRNSretina did not lower the VCT compared with the no tRNS condition when retested on the VCT data in session 3 (t(18) = 0.12, p = 0.45, MD = 1.02 ± 24.57%, and t(18) = −0.17, p = 0.44, MD = 2.91 ± 26.51%; retina in the first blocks of Retina and V1+Retina sessions .In the third session we also retested the effects of individually optimized tRNS intensities defined in V1 and Retina sessions. The effect of ind-tRNSTo characterize the exposure of the two stimulation conditions, namely, V1 and the retina stimulation, for different current intensities , we compared the mean and standard deviation (SD) of the total E-field in six regions along the retino-cortical pathway, namely the retina, optic nerve, optic chiasm, optic tract, posterior thalamus (including LGN), and V1 area. The results are presented in According to the simulation predictions, Oz and Cz configuration efficiently targeted the V1 region (0.25 ± 0.06 V/m) and led to average stimulation of 0.016 ± 0.01 in the retina for the medium (1 mA) current intensity A,D. By cV1 and tRNSretina and tRNSV1+retina across three experimental sessions. We found consistent tRNS-induced enhancement of visual contrast detection during V1 stimulation  found by V1. Moreover, the 4-AFC task protocol used in our study was shown to be more efficient for threshold estimation than commonly used 2-AFC  which is consistent with a SR mechanism. Note, that enhancement in visual detection performance was reflected in decreased VCT in relation to the no stimulation baseline  results in consistent online enhancement effects when retested on the independent data set (VCT in second block) within the experimental session  applied to the retina to investigate the efficacy of different carrier frequencies to induce phosphenes. AM-tACS waveforms comprised of different carrier  and modulation frequencies . They found that from the conditions using different carrier frequencies only the lowest one was able to induce phosphenes . Note, however, that the characteristics of the current waveform (variable intensities and frequencies) might be challenging for reliable simulation of the E-field induced by tRNS. Additionally, special attention should be drawn to the feasibility and safety when higher stimulation intensities are delivered over the temples, as the skin around the eyes might be sensitive.In summary, we found no evidence that tRNS affects contrast detection at the retinal level. This is interesting from a methodological perspective since it may rule out that applying tRNS over V1 elicits confounding effects in the retina, as previously discussed for tACS experiments .V1, nor ind-tRNSretina were replicated  introducing noise at different levels of the visual system in short time breaks was not beneficial for the task performance, or (2) using a range of tRNS intensities, as in the first and second session might have increased the probability of acute noise benefits in comparison to stimulation with only one preselected intensity.Importantly, the overall design of the third session (V1+Retina) was different from the previous two regarding the stimulation conditions. Here, the preselected stimulation conditions of ind-tRNSV1 or ind-tRNSretina was not replicated in session 3, it is not possible to draw conclusions about the simultaneous effect of V1 and the retina stimulation  because of the COVID-19 pandemic  could hamulation A,B.V1 and tRNSretina. Finally, we found that the individual optimal tRNS intensity applied to V1 to enhance contract detection appears to vary across sessions. The appropriate adjustment of optimal tRNS intensity is therefore important to consider when designing tRNS protocols for perceptual enhancement.In conclusion, our study confirms previous findings that tRNS might enhance visual signal processing of cortical networks via the SR mechanism . When pr


Age-related hearing loss, or presbycusis, is a common cause of hearing loss in elderly people worldwide. It typically presents as progressive, irreversible, and usually affects the high frequencies of hearing, with a tremendous impact on the quality of life. Presbycusis is a complex multidimensional disorder, in addition to aging, multiple factors including exposure to noise, or ototoxic agents, genetic susceptibility, metabolic diseases and lifestyle can influence the onset and severity of presbycusis. With the aging of the body, its ability to clean up deleterious substances produced in the metabolic process is weakened, and the self-protection and repair function of the body is reduced, which in turn leads to irreversible damage to the cochlear tissue, resulting in the occurrence of presbycusis. Presently, oxidative stress (OS), mitochondrial DNA damage, low-grade inflammation, decreased immune function and stem cell depletion have been demonstrated to play a critical role in developing presbycusis. The purpose of this review is to illuminate the various mechanisms underlying this age-related hearing loss, with the goal of advancing our understanding, prevention, and treatment of presbycusis. Age-related hearing loss (ARHL), or presbycusis, is the most common sensory deficit affecting aging adults . ARHL tyAccording to a 2012 estimate by the World Health Organization, about 164.5 million people over the age of 65 suffer from hearing impairment worldwide, accounting for about 33% worldwide in adults older than 65 years . The prePresbycusis is a complex chronic aging disease that results from the gradual accumulation of deleterious biological lesions and auditory system dysfunction . With thThe cochlea is a spiral-shaped cavity composed of three liquid-filled compartments, scala media, scala tympani and scala vestibuli, which can convert the mechanical vibration caused by sound waves into electrical signals during sound transmission and is an important target organ for presbycusis. Scala media contains endolymph with high potassium and low sodium and is sandwiched by scala tympani and scala vestibuli containing perilymph with low potassium and high sodium. The endolymph in the scala media contains a positive voltage of +80 to +100 mV , which is generated by the potential difference between the endolymph in scala media and the perilymph in scala tympani . The strAuditory information transmission is a complex process, and the cochlea is an important organ in this process. The shear motion caused by acoustic vibration causes the cilia of hair cells to bend or deflect, which in turn opens potassium channels at the top of hair cells, allowing potassium ions in the endolymph to flow into the hair cells to produce depolarization. Depolarization of hair cells causes calcium channels to open in cells and calcium ions to influx, which in turn prompts hair cells to release neurotransmitters into the synaptic cleft of the hair cells and auditory neurons . Damage According to postmortem histopathological studies, a variety of pathological changes occur in the inner ear of patients with presbycusis, such as the atrophy of the stria vascularis (SV) and loss of fibrocytes of the spiral ligament (SL) in the lateral wall of the cochlea , decrease of sensory hair cells (sensory presbycusis) and degeneration of the auditory nerve  . The cocHowever, in reality, affected by various pathogenic factors, presbycusis can cause lesions in multiple parts of the cochlea, showing a “mixed” pathology . In addiPresbycusis is a disease with genetic susceptibility. According to twins studies and longitudinal studies of family cohorts, its heritability is small to moderate, with a heritability indices of between 0.35 and 0.55 . Unlike GRM7 may lead to the accumulation of neurotransmitters in synaptic connections, thereby altering the susceptibility to presbycusis (UCP2), Superoxide dismutase 2 (SOD2) and N-acetyltransferase 2 (NAT2) (Genome-wide association study (GWAS) is widely used for genetic composition analysis of presbycusis, and many candidate genes have been found to be associated with presbycusis . These gsbycusis . Genetic2 (NAT2) . Additio2 (NAT2) .TMC1 variant was previously thought to be associated with progressive postlingual hearing loss and profound prelingual deafness. However, in a recent study, in vitro transfection and in vivo animal models that the heterozygous pathogenic variants of TMC1 can cause presbycusis in a single-gene form, which updates our understanding of the inheritance pattern of presbycusis and provides a basis for potential inner ear treatments.Monogenic deafness-causing genes, especially those that cause delayed-onset deafness, may also be associated with presbycusis. Noise is the second most common cause of hearing loss other than old age, and noise-induced hearing loss (NIHL) is considered a common occupational disease, with a high incidence in occupational workers who have been exposed to noise for a long time, such as workers in textile, mining, and heavy engineering industries . Both agNoise damage to the auditory system is affected by intensity and duration of noise exposure and can cause permanent threshold shifts (PTS) or temporary threshold shift (TTS) . Both loAminoglycoside antibiotics and chemotherapy drugs such as cisplatin and carboplatin can cause degenerative changes in the cochlea and hearing loss . AdditioMetabolic diseases are a cluster of diseases or disorders that disrupt normal metabolism, including high blood sugar (hyperglycemia), increased blood pressure (hypertension), excess fat around the waist (obesity), and abnormal levels of cholesterol or triglycerides (dyslipidemia). In recent years, under the influence of unhealthy diet and lifestyle, the incidence of metabolic diseases and its components are on the rise, and it is most common in the elderly . PresbycLifestyle effects on hearing are diverse, with studies showing that both smoking and passive smoking increase the risk of hearing loss, while moderate alcohol consumption has a protective effect on hearing . Diet anReactive oxygen species (ROS) are highly reactive chemicals produced during mitochondrial respiration or cellular response to endogenous and exogenous factors, mainly including superoxide anion (O2-), hydrogen peroxide (H2O2), hydroxyl radical (OH-) and nitric oxide (NO-) . ROS canThe cochlea is an energy-intensive organ in which mitochondria provide energy for their sodium-potassium pump activity and ion transport through oxidative phosphorylation, while producing large quantities of ROS. The aggregation of ROS in the cochlea can lead to mutations in the mitochondrial genome, resulting in mitochondrial DNA (mtDNA) damage . MitochoHowever, as the body ages, the production and function of antioxidant enzymes decrease, and ischemic and hypoxic damage from local vascular lesions in the cochlea leads to increased production of ROS . As a reInflammaging is chronic and low-grade inflammation of tissues and organs that occurs during aging and can lead to conditions as diverse as cardiovascular disease, diabetes, and neurodegenerative diseases . VariousMacrophages are a key part of the innate immune system, presented in the cochlear spiral ligament, the auditory nerve, and the organ of Corti. Activated macrophages transform from highly branched morphology to amoeboid shape and can phagocytose cellular debris or pathogens, which are critical for maintaining the homeostasis of the cochlear microenvironment . In addiThe intestinal tract contains a large number of microorganisms and their genetic material, and gut dysbiosis may also contribute to inflammaging. In addition to the high-fat diet can lead to the development of cochlear inflammation . As the The spiral ligament is a component of the potassium ion transport system in the lateral wall of the cochlea, which contains five types of fibrocytes, and its normal function is crucial for the maintenance of the EP . Unlike The management of presbycusis should first focus on prevention and avoid exposure to risk factors. While we cannot prevent aging, nor can we change our genetic background, we can minimize noise exposure, wear earplugs in noisy environments, and avoid ototoxic medications . ElderlyTreatment of presbycusis still relies clinically on hearing amplification and cochlear implantation. Air conduction hearing aids are commonly worn in patients with mild to moderate hearing loss, active middle ear implants can be used in patients with moderate to severe hearing loss, and cochlear implants should be considered in patients with severe to profound hearing loss . HoweverIn recent years, some researchers have begun to explore the treatment of presbycusis with antioxidants, anti-inflammatories, neurotrophins and other drugs . StudiesPresbycusis is a common chronic disease occurring in the process of aging, which is the result of the interaction of various extrinsic and intrinsic factors under the genetic background. With the aging of the body, the function or number of immune functions, antioxidant enzymes and self-repairing stem cells that are closely related to the body’s self-protection decline, resulting in the accumulation of inflammatory cytokines, reactive oxygen species and tissue cell damage in the body. Therefore, under the action of chronic inflammation and oxidative stress, irreversible damage occurs to the cochlear stria vascularis, spiral ligament, sensory hair cells and auditory nerve fibers, and then lead to the occurrence of presbycusis.Mitigating exposure to risk factors is essential for the prevention of presbycusis. The clinical treatment of presbycusis is still mainly based on wearing hearing aids and cochlear implants, but various drugs launched according to its pathogenesis are also undergoing clinical research. The in-depth exploration of the pathogenesis of presbycusis provides a reference for potential drug treatment and clinical intervention.WY: Writing – original draft, Methodology. XZ: Writing – original draft, Methodology. RC: Visualization, Writing – review & editing. JF: Validation, Writing – review & editing.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. 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