Some studies have already explored the relationship between diabetes and hearing loss; however, this relationship has still not been well established, especially due to methodological limitations related to lack of control for confounders. The aim of this study was to analyze the association between self-reported hearing impairment and diabetes among adults in Brazil, controlling for sociodemographic and occupational exposure to ototoxic agents.This is a cross-sectional study based on data collected by the National Health Survey of 2013 in Brazil. A total of 60,202 individuals aged≥18 years were interviewed. Crude and adjusted prevalence ratios were calculated using the Poisson regression model with robust estimation of the variance. All analyzes were performed considering the appropriated weights imposed by the complex sample design.crude = 2.92; 95%CI: 2.75–3.11) and also in the analysis adjusted for gender, age, skin color, schooling, smoking, alcohol consumption and occupational exposure .Hearing loss prevalence was 2.56% (95%CI: 2.34–2.79). It was higher in males, older age groups, white and individuals with lower levels of schooling. Diabetes was positively and significantly associated with hearing loss in the crude analysis (PRThe present results suggest that individuals with diabetes have higher prevalence of hearing impairment. There is the need of longitudinal studies to investigate if diabetes is a risk factor to hearing impairment. Estimates indicate that more than 5% of the population, approximately 360 million people in the world, have hearing impairment in some extent . DisabliOn the other hand, diabetes has been a major cause of morbidity and mortality and one of the four major chronic diseases identified by the World Health Organization (WHO) as a focus for control and prevention . It was Audiometry is the gold standard for the detection of hearing loss but performing it in population surveys becomes complex and costly. This procedure requires booth, audiometric equipment and trained personnel. Thus, self-referred population surveys that verify the prevalence of hearing impairment through a simplified questionnaire may be an alternative and have been ratified in studies that found acceptable sensitivity and specificity values when compared to the gold standard .Studies with self-declared surveys about the hearing condition can provide clues about temporal trends in the prevalence of hearing loss, contributing to the identification of groups at greater risk. They are also characterized as faster and more economical surveys to provide population estimates, since they minimize fieldwork time and costs with equipment and trained professionals .These two public health problems, namely hearing impairment and diabetes, seem to be associated, especially over the fourth decade of life. Authors justify that hearing loss and its associated factors, such as tinnitus and vertigo, may be associated with diabetes due to microcirculatory insufficiency regarding a vascular occlusion by embolism, hemorrhage or vasospasm which, in turn, would be due to a hyperviscosity syndrome or microangiopathy (due to diabetes or even due to hypertension) , 7.The global burden of diabetes is expected to increase due to higher longevity and life style changes in the population. Those characteristics will adversely affect the patient’s quality of life and their ability to live independently . Also, cSurveys already conducted –13 have Pesquisa Nacional de Saúde - PNS) is a survey with national representativeness from which it is expected consistent data in order to contribute to the elaboration, evaluation and monitoring of actions and health programs for the Brazilian population. It is expected that hearing care and attention to diabetes will gain greater attention after the results provided in this study.The National Health Survey  and diabetes among adults in Brazil, based on self-reported data from the National Health Survey (PNS) of 2013 considering adjustments factors .This is a cross-sectional study with data from the PNS, a household survey carried out in Brazil in 2013 by the Brazilian Institute of Geography and Statistics (IBGE) in partnership with the Ministry of Health (MS) and the Instituto Oswaldo Cruz Foundation (Fiocruz).The targed population was adults aged 18 years or over living in private households throughout the Brazilian territory, excluding the special census tracts . Cluster sampling was used, divided into three stages, with the census tracts as primary units, households as secondary units, and a tertiary unit composited by an adult (≥18 years old) selected from each household to answer the applied questionnaire. The detailed methodology is described in a previously published article , 15.A total of 81,167 households were visited, of which 69,994 were occupied. There were 64,348 home interviews and 60,202 individual interviews with the selected resident in the household, which resulted in a non-response rate of 8.1% , 15., between August 2013 and February 2014. The interviewers were adequately trained to address the interviews and include the responses in the PDA [Data collection was performed by the IBGE team, that is, interviewers with the support of supervisors and coordinators. The training program and material of the field staff was done in partnership with the MS. The training of coordinators and supervisors for the data collection was on-site and the interviewers were trained by the coordinators and supervisors. Interviews were conducted with the help of handheld computers - PDA  the PDA .The PNS questionnaire is divided into two parts: the first one (home interview) consists of 11 modules and is answered by a representative of the domicile who responds by all residents of the household. The second part  is composed of 9 modules and is answered by the resident selected randomly among all eligible adult residents of the household, and consists of questions only for this resident.“Does_______ have hearing loss?”) defined as binary (“yes” or “no”) and was answered in the household interviews. All individuals that had responded as being hearing impaired were included in the SHI population. The main exposure considered is the self-reported diagnosis of diabetes: “Has a doctor ever given you the diagnosis of diabetes?”, defined as binary (women who responded only during pregnancy were considered as “no” for diabetes) and it was not answered by those who said they had never made blood test to measure blood glucose. The adjustment factors considered were: sex , age group , skin color , schooling , smoking (“yes” or “no”), alcohol consumption (defined in two categories: “yes” or “no”) and occupational exposure .SHI was the outcome  were calculated using the Poisson regression model with robust estimation of the variance. All analyzes were performed considering the effect of the study design. Analyzes were performed using the survey and sandwich packages and the R Version 3.4.1.Table Table black = 0.57; 95%CI:0.54–0.60 and PRothers = 0.82; 95%CI:0.77–0.87), level of education , non-consumption of alcohol  and occupational exposure  are factors positively associated with SHI. The smoking factor was not significantly associated  with SHI.Table crude = 2.92 (95%CI: 2.75–3.11). The association between diabetes and SHI was adjusted for sex, age, race or skin color, educational level, smoking, alcohol consumption and occupational exposure remained significant   with PRThis study presentes the SHI prevalence and its association with diabetes. The hearing impairment prevalence was higher in men , from the sixth decade of life , among those who declared themselves as white skin or color  and among adults with less schooling .Population studies on the prevalence of hearing impairment are not numerous, especially when dealing with the Brazilian population and, when available, present different methodologies, an aspect that makes comparison between the findings difficult.The estimated SHI prevalence was 2.56% (95% CI:2.34–2.79). This value is less than some national studies, as IBGE Census , in whicThe National Health Interview Survey (NHIS), 2010 , researcIn the cross-sectional study by Hong et al.  with datA higher prevalence of hearing impairment among men than among women has been reported in other studies in Brazil , 20, 21 This study showed that, the older the individual, the higher the prevalence of hearing loss. These results were corroborated by other studies conducted in other countries such as the United States , 19, KorIt is estimated that the proportion of individuals aged 60 and over ranged from 5% in 1960 to 8.6% in 2000 and will increase to 14% by 2025, reaching a significant proportion in developed countries [Minor differences were observed for skin color or race, with a higher prevalence of hearing loss among adults who declared themselves as white. These results meet the NHIS research in 2012  and NHANIn a study that aimed to analyze self-reported differences between blacks and whites , regardiIn the present study, people with less education tend to have a higher prevalence of hearing impairment , with hievaluated the global burden of hearing loss induced by occupational noise, concluding that occupational noise is an important risk factor for hearing loss in workers at most ages.As to the type of hearing impairment, the acquired one was the most prevalent. Across the world, 16% of incapacitating hearing loss in adults is attributed to occupational noise, ranging from 7 to 21% in the various subregions. The effects of noise exposure are higher for men than for women in all sub-regions and higher in developing regions . In a stConcerning the involvement of the ears, 56.1% of those who self-referred hearing loss have deafness or reduced hearing in one ear. In American study  in speecAbout the degree of limitation that hearing impairment brings, the present research showed that, for 37.0% (95% CI: 33.5–34.7) of those who have it, it is not a limitation. A percentage of 74.5% reported having no difficulties in leisure activities, 88.6% said they did not need help in daily activities, and 63.3% reported having no need for assistance, although they did not have statistical significance .In this population who reported hearing impairment 87.0% (95%CI: 84.1–89.4) have not made use hearing aids. The hearing rehabilitation service has been used by 16.4% (95%CI: 12.8–20.9) of those who use this device.n = 45) have used it. When asked why they have not used the hearing aid, 8.6% said that although indicated, they had not got used to it and 8.0% had not acquired it because of financial problems. Analyzing the ways of acquiring the device, 78.8% had used private resources and 16.9% had acquired it through the Unified Health System. On receiving training for the use of hearing aids, 87% had received it and 81.4% had been followed up for control of the hearing aid.In a research of Cruz et al.  performeSmoking not was significant in this study, but one study found nicotinic receptors in the hair cells of the cochlea, suggesting that smoking has detrimental effects on the function of hair cells due to possible action during auditory neurotransmission . In addiOn the other hand, alcohol consumption was a protective factor for hearing loss in the univariate analysis. In a population-based cross-sectional study of 164,770 adults in the UK aged 40–69 years who completed the “speech-in-noise” hearing test, those who were drinkers were approximately 40% less likely to have a hearing loss than those who do not drink .et al. [The study of Upileet al.  suggestset al. , conductAs for the occupational exposure variable , it proved to be associated with hearing impairment. Noise is the most common occupational exposure addressed in studies and is associated with hearing loss related to work. A survey of US universities gardeners concluded that these professionals have been exposed to excessive noise, exceeding the limits of 85 dB, which can be effectively reduced through careful programming encouraging the use of personal protective equipment . Betweenet al. [A study with municipal workers of solid waste landfills showed that there were several occupational hazards for these, including exposure to noise, dust, toxic gases, heat, heavy metals and volatile organic compounds . Mohammaet al.  found thAnother study with municipal workers of solid waste landfills that aimed to investigate occupational hearing loss divided the sample into 3 groups: group 1 of 63 workers without exposure to occupational risks (control group); group 2 of 84 workers with little or short exposure to occupational hazards; and group 3 of 100 workers with continued exposure to occupational hazards. Both noise and total volatile organic compounds were significantly higher in workplaces for group 3. Significantly worse auditory thresholds at frequencies of 2, 3 and 4 kHz were found in group 3 compared to group 1 and group 2. The rate of prevalence of hearing loss was 23.5%, being the highest in group 3 (36.0%). The odds ratio of municipal workers of solid waste landfills associated with hearing loss was 3.39 (95% CI: 1.28–8.96) .adjusted = 1:46: 95%CI: 1.32–1.61). In a study that evaluated predisposing factors for hearing loss [mellitus showed significantly worse hearing results in 0.5, 1 and 6 kHz, which is confirmed in the population-based study of 16,040 individuals conducted in Korea [This study indicates that individuals with diabetes have 46% higher risk for hearing loss  for mild impairment at high frequencies and 1.24 (95%CI: 1.05–1.45) for moderate to severe impairment at high frequencies. Only in these two cases it was observed statistical significance.A recent meta-analysis has shown that the odds ratio of hearing impairment to the diabetic participants was 2.15 (95%CI:1.72–2.68) compared with non-diabetic participants and it is likely to be regardless of the effect of aging or the noisy environment to which one is exposed .Another meta-analysis identified patients with type 2 diabetes with a significantly higher incidence of mild hearing loss compared to controls; thresholds in the average of pure tone audiometry were higher in diabetics for all frequencies, but were more clinically relevant in 6 and 8 kHz .In a population survey of Bainbridge et al.  with datThe fact that the hearing impairment diagnosisis is self-reported, considering the perception of each person, can imply that mild hearing impairments are not identified as moderate or severe hearing impairmentby the subject, causing a possibility of measurement bias. Considering that most hearing impairments are progressive, a proportion of survey respondents may not have identified that has such a complaint, which explains the proportion of difference compared with other surveys using pure tone audiometry to estimate the prevalence of hearing impairment or any type of hearing impairment that could cause any disconfort.Another fact that must also be taken into account when considering the prevalence of hearing impairment and its association with risk factors is whether it is congenital or acquired. In this study, the acquired hearing loss was more prevalent, making us think that the occupational exposure and the diseases acquired throughout life may influence the occurrence of this outcome, i.e., the more unhealthy the workplace is and the greater the diseases associated with hearing loss the person is exposed to, such as diabetes, the greater the prevalence of hearing impairment.In the general population of PNS, the prevalence of diabetes was 6.2% (95% CI: 5.9–6.6), with higher prevalences among women, individuals over 60 years of age, non-smokers, non-alcoholics and people with lower educational levels. Among SHI cases, a similar profile was observed, except for the prevalence of diabetes in alcohol use, since there was no difference between use and non-use and in the educational variable, since higher prevalences were obtained in individuals with higher levels of schooling.To diabetes there can be a difference between individuals with type 1 or type 2 diabetes, but considering that about 90.0% of cases are of type 2 diabetes , especiaThe strengths of this study are the following: the size of the sample, because it has great statistical power and is representative of the Brazilian population; the response rate to the survey, which was very satisfactory (92%) and; with the weights, the results can be extrapolated to the entire Brazilian population, and perhaps the most important point is about the confounding variables, so that the factors associated with hearing loss were explained as clearly as possible, a factor observed in the multivariate analysis. This is the first Brazilian study we know that this aspect related to occupational exposure, such as noise, chemicals and solid waste, was considered in the multivariate analysis, along with tobacco and alcohol consumption, factors previously reported to be associated with hearing impairment.On the other hand, that are several limitations of this study. The research refers to a cross-sectional study, and conclusions about statistical associations may not be causal, and reverse causality cannot be ruled out. In addition, as the exposures and outcome were based on self-reports, there may be a reporting bias, which may lead to inflated associations due to the variance of the common method.The results of the present study suggest that individuals with diabetes has higher prevalence of hearing impairment. The investigation of the association between non-communicable diseases, such as diabetes, and hearing impairment should be continued in order to provide a clearer understanding of the etiologic risk factors related to hearing impairment, resulting in the establishment of better actions for vulnerable populations. Thus, public health resources can be better applied, contributing to the development of public policies for the prevention of hearing loss. This study may also foster more targeted and planned research to investigate factors interconnected between the various short comings.


A 42-year-old female known with osteogenesis imperfecta (OI) was referred to our department with complaints of deteriorating hearing loss. The medical history, besides some limb fractures, secondary to the OI, was negative. During clinical examination, a sensorineural hearing loss was confirmed bilaterally.A cone-beam computerized tomography (CBCT) was performed and revealed an otic capsule demineralization at the level of the antefenestral fissula (white arrows) and the pericochlear area (black arrows) on either side, suggestive of bilateral otosclerosis  having a lethal outcome. Mutations in the COL1A1 and COL1A2 genes are responsible for 90% of the cases. Multiple detector computed tomography (MDCT) is the golden standard to demonstrate demineralization of the otic capsule. The very high spatial resolution (125 µm), better image quality and lower radiation dose make CBCT a very tough competitor for MDCT. A schematic axial representation at the level of the incudomalleal joint is added depicting CBCT findings in OI compared to normal subjects (Figure The differential diagnosis of bilateral otic capsule hypoattenuation in the temporal bone includes osteogenesis imperfecta, otosclerosis, otosyphilis, Paget’s disease and dysplastic bone diseases. As no cure exists for OI, treatment for bone involvement is symptomatic. Treatment options for hearing loss include bone-anchored hearing aids, cochlear implants and stapes surgery.In conclusion, whenever a physician encounters a patient with osteogenesis imperfecta and hearing loss, a temporal manifestation of osteogenesis imperfecta must be kept in mind.The authors declare that they have no competing interests.


In vitro, CDKL5 overexpression enhanced invasion, growth and migration of glioma cells, and stimulated the phosphoinositide 3‐kinase (PI3K)/AKT axis. Furthermore, CDKL5 overexpression in vivo promoted glioma proliferation, whereas CDKL5 knockdown had opposing effects. The effect of CDKL5 on drug resistance was eliminated if the PI3K/AKT axis was suppressed, and cisplatin combined with the PI3K/AKT suppressor XL147 remarkably prohibited proliferation in xenografts overexpressing CDKL5. Collectively, our findings suggest that CDKL5 acts through the PI3K/AKT axis in glioma cells, and indicate a possible role for CDKL5 in glioma therapy.Gliomas, the most prevalent cancer in the central nervous system, are characterized by high morbidity and mortality, emphasizing the need to understand their etiology. Here, we report that cyclin‐dependent kinase‐like 5 (CDKL5) is highly expressed in gliomas, and CDKL5 overexpression promotes invasion, proliferation, migration and drug (β‐lapachone) resistance of glioma cells.  in vivo by stimulating the phosphoinositide 3‐kinase/AKT axis. This research suggests that cyclin‐dependent kinase‐like 5 may have potential in the assessment of clinical outcome and treatment of gliomas.Cyclin‐dependent kinase‐like 5 promotes the proliferation, migration, drug resistance and invasion of glioma cells, which contributes to glioma growth  Moreover, the promising etiology of gliomas was recognized.2 in Dulbecco’s modified Eagle’s medium  containing 10% FBS  at 37 °C.The human glioma cell lines U87  and U251 were acquired from the Type Culture Collection of the Chinese Academy of Sciences  and subsequently preserved in 5% COTwenty‐seven patients received clinical and histological diagnoses of gliomas at The First Affiliated Hospital of Dalian Medical University. Fully written informed consent was acquired, and our research was approved by the Ethics Committee of The First Affiliated Hospital of Dalian Medical University. The study methodologies conformed to the standards set by the Declaration of Helsinki. Cerebral tissue specimens were acquired from five patients who had encountered intracerebral hemorrhage. All samples were kept at −80 °C.2O2 with 1% BSA in Tris‐buffered saline (TBS). The specimens were incubated overnight with murine IgG isotype antibody or mouse anti‐human CDKL5 IgG at 4 °C in a humid chamber. The slices were covered with goat anti‐mouse IgG antibody conjugated with peroxidase  after three washes with TBS.Paraffin slices (5 μm) of glioma and normal cerebral tissues were subjected to dehydration using a graded concentration series of ethanol before incubation in HTRIzol  was used to isolate total RNA from tissues, which was purified using the RNeasy Mini Kit . Superscript III Kit (Life Technologies) was applied for reverse transcription. cDNA was evaluated by quantitative PCR. Transcription was quantified and evaluated by RT‐PCR using the SYBR Green PCR Supermix kit . Every procedure was carried out in triplicate. Real‐Time StatMiner  was used to assess gene expression.Plasmids CDKL5‐pcDNA3.1 (CDKL5) and pcDNA3.1 (vector) were acquired from Shanghai GenePharma Co. Ltd. . U251 cells were seeded in six‐well plates 1 day before transfection. Transfection admixture was generated by adding 4 µg plasmid DNA and 3 µg TurboFect reagent  to DMEM/F12 without serum. The admixture was supplemented to the culture media, and the cells were further incubated for 6 h. In terms of siRNA transfection, U251 cells were transfected with 20 nmol control GL2 siRNA targeting the luciferase gene  or siRNA oligonucleotides targeting CDKL5 using Lipofectamine RNAiMAX (Life Technologies).4 cells·mL−1). MTT assay was carried out 48 h after transfection. Cell survival was assessed by adding 10 μL MTT reagent to every well, and cells were further incubated for 4 h at 37 °C. The cells were examined using a microplate reader at 570 nm . Every experiment was carried out three times independently.Cell survival was evaluated using the 3‐‐2,5‐diphenyl‐tetrazolium bromide (MTT) assay. Cells were seeded in 96‐well plates . Cells in DMEM containing 10% FBS were seeded to the bottom chambers. Cells at the top surface were scraped off after 48 h of incubation, whereas those at the bottom were fixed, stained and quantified.The Transwell assay was performed to evaluate cell migration. Cells were suspended in DMEM containing 1 mg·mL5 cells in each chamber) in the top chambers and incubated for 24 h. FBS (20%) served as a chemoattractant and was added to the chambers below. A cotton swab was used to eliminate noninvading cells on the top surface after incubation, whereas invading cells at the bottom were fixed with 100% methanol before staining with 1% crystal violet. Invading cells were quantified using a microscope, and six randomly selected visual fields were assessed for every assay.Transwell chambers that were covered with Matrigel were used to assess cell invasion. Transfected cells were seeded  was used to assess the distribution of cell phase.Cells were starved for 12 h in preparation for synchronization before reactivation for 24 h with 10% FBS. Cells were fixed in 75% ethanol and treated with the Cell Cycle Detection Kit. A FACSCalibur flow cytometer  was used to categorize the cells. g. The sediment was resuspended with binding buffer. Propidium iodide and FITC/Annexin V were supplemented while the mixture was incubated for 10 min at 37 °C. A FACScan flow cytometer  was used to evaluate fluorescence signals.Apoptosis was assessed by flow cytometry (FC). The supernatant was eliminated after centrifugation for 5 min at 1000 −1 puromycin incubation for 7 days. Nude male BALB/c mice aged 4 weeks were subcutaneously injected with approximately the stable clones of U251 cells (4–6 × 106 cells), transfected with CDKL5, in their flanks regardless of the presence of infection. Mice were treated intraperitoneally with 5 mg·kg−1 cisplatin and 40 mg·kg−1 XL147  two times per week for 30 days . Every group consisted of five mice, which were executed after 30 days, and the malignancies were cut off and weighed.Procedures related to animals were approved by the Ethical Committee of The First Affiliated Hospital of Dalian Medical University. The CDKL5 plasmid was constructed into the lentivirus vector LV‐3 (GenePharma). Stable cell lines with CDKL5 overexpression were selected with 4 μg·mLLysis buffer  was applied to homogenize cell lysates and tissues, whereas protein quantification was carried out using the Bradford assay (Bio‐Rad). Protein evaluation was performed using SDS/PAGE. Tris/HCl polyacrylamide gels  were used to isolate proteins, which were moved to polyvinylidene fluoride membranes (Millipore). The blots were incubated overnight with primary antibodies  at 4 °C in TBS/Tween. Thereafter, the blots were incubated with secondary antibodies conjugated with horseradish peroxidase. Enhanced chemiluminescence plus detection reagent  was used to examine immunoreactive bands, which were assessed by the Omega 16ic Chemiluminescence Imaging System .t‐test and ANOVA before Tukey’s post hoc analysis. Statistical significance is indicated by P < 0.05.Results are displayed as mean ± SEM (standard error of the mean). Differences between groups were measured by two‐tailed, unequal‐variance Student’s We examined CDKL5 in 27 normal cerebral specimens and gliomas to investigate the promising influence of CDKL5 on glioma generation and progression. CDKL5 transcription was noticeably upregulated in glioma tissues compared with that in normal tissues Fig. A. ImmunoWe then examined the impact of CDKL5 on the migration and invasion of glioma cells. Noncoated Transwell chambers were used to evaluate the migration capability of U251 cells. It was shown that excessive CDKL5 expression remarkably promoted cell migration  displayed remarkably reduced proliferation in comparison with that of the control group Fig. A, whereaWe additionally explored whether CDKL5 regulated the malignancy counteraction activity of β‐lapachone (β‐lap), which served as an innovative malignancy‐counteracting agent that has been proved to stimulate various reactions of apoptosis in malignant cells. We evaluated cytotoxicity using the Cell Counting Kit‐8 and observed that cell survival was suppressed in the presence of β‐lap Fig. D. ExcessThe PI3K/AKT axis participates in the modulation of cell proliferation and invasion in vivo. PI3K inhibitor XL147 significantly reduced the CDKL5‐induced phosphorylation level of AKT in vivo (Fig. Nude male BALB/c mice were injected with U251 cells with CDKL5 plasmid in the flanks, and malignancies were weighed 30 days later to explore whether CDKL5 reinforced glioma proliferation Our research showed that CDKL5 expression was promoted in glioma specimens in comparison with that in normal specimens. The activity of CDKL5 in glioma cells was studied by excessive expression and KD assays. We discovered that excessive CDKL5 expression reinforced drug resistance, migration, proliferation and invasion in glioma cells, whereas CDKL5 KD resulted in the opposite effects. CDKL5 enhanced the stimulation of the PI3K/AKT axis, which subsequently participated in glioma generation. Collectively, our findings reveal that CDKL5 can modulate glioma proliferation, and that the PI3K/AKT axis participates in this reaction. The results of this research throw light upon both the influence of CDKL5 on gliomas and strategies of glioma therapy.in vivo but also in vitro. Furthermore, CDKL5 KD stimulated counteracting effects on malignancy growth. These findings can assist us in understanding the etiology of the oncogenic effect of CDKL5 and alter our perspective of its impact as a candidate treatment agent. In vivo findings indicated that CDKL5 enhanced glioma generation by stimulating the PI3K/AKT axis.Gliomas are one of the most fatal malignancies in the central nervous system, with glioblastoma being the most common form, which features poor median survival of 15 months and extreme aggressiveness in vivo. The results of our research suggested that CDKL5 reinforces the generation of gliomas through the PI3K/AKT axis.The PI3K/AKT axis is related to metastasis and glioma development in vivo by stimulating the PI3K/AKT axis. This research emphasizes the promising effect of CDKL5 on the assessment of clinical outcome and treatment application of gliomas.In summary, our research demonstrated that CDKL5 expression is reinforced in gliomas, and that it affects the proliferation, migration, drug resistance and invasion of glioma cells. Furthermore, CDKL5 enhances the generation of gliomas The authors declare no conflict of interest.ZJ and HW conceived the study and designed the experiments. ZJ, TG and HW contributed to the data collection, performed the data analysis and interpreted the results. ZJ wrote the manuscript. ZJ and HW contributed to the critical revision of the article. All authors read and approved the final manuscript.


The number of steps required to regain balance is an easily obtainable clinical outcome measure. This study assessed whether number of steps during loss of balance could identify older adults with hearing loss who have balance deficits. We aimed to answer two questions: 1) Does hearing loss negatively affect the ability to regain balance, as reflected by an increased number of steps needed to respond to a perturbation while simultaneously attending to speech-in-noise; and 2) Do hearing aids improve balance control, reflected by a decrease in number of steps needed to regain balance?20 young adults and 20 older adults with normal hearing, and 19 older adults with hearing loss performed an auditory-balance dual-task. Participants were asked to listen and repeat back sentences from a standardized audiology test, while simultaneously responding to backward surface translations. Outcome measures were performed on the auditory test and number of steps needed to regain balance. Repeated measures ANCOVA models were run in using group, time, hearing levels, and perturbation levels as predictors.Auditory scores confirmed difficulty hearing speech-in-noise in older adults with hearing loss and no hearing aids, and in young and older adults with normal hearing and simulated hearing loss. Results showed that group, auditory and balance conditions are significantly related to both outcomes measures and time is not significant for steps. Older adults with hearing loss had a significant increase in number of steps needed to regain balance compared to young adults and older adults with normal hearing.Number of steps may be an appropriate clinical assessment tool for identifying fall risk in older adults with hearing loss. Further research needs to be performed to identify proper assessments and treatment interventions for older adults with hearing loss who have balance deficits. Falls are a common problem with adults 65 years and older. One-third of older adults fall annually, costing the United States government approximately 34 billion dollars to cover direct medical expenses for procedures and hospitalization ,2. FallsAnother common problem plaguing older adults is hearing loss. Age-related hearing loss affects greater than 60% of people aged 70-79 and 80% of those 80 and older . In the Moreover, recent evidence has also linked hearing loss to balance deficits in older adults through fall-risk associated assessments, such as slower walking speed and poor Romberg scores ,12. ThesWe aimed to answer two questions: 1) does hearing loss negatively affect the ability to regain balance as reflected by an increased number of steps needed after a perturbation, and 2) do hearing aids reverse this effect and improve balance control, reflected by a decrease in number of steps needed to regain balance.We hypothesize older adults with hearing loss will take a greater number of steps during an unexpected loss of balance, compared to young adults with normal hearing and older adults with normal hearing.Twenty-five young adults, 33 healthy older adults with normal hearing, and 22 older adults with hearing loss were verbally informed about the research study and voluntarily agreed to participate through Institutional Review Board (IRB)-approved informed consent. All participants were phone screened prior to enrollment to ensure no visual, vestibular, somatosensory, auditory, health conditions or balance impairments existed that would restrict ability or confound results of the study. Participants were excluded if they had a history of motion sickness/dizziness, or were currently taking medications that affect balance.Participants underwent cognitive and sensory screening to ensure no undiagnosed cognitive or sensory impairments were present. Five young adults, 13 older adults with normal hearing, and three older adults with hearing loss were excluded due to either undiagnosed cognitive or sensory impairments, or withdrew from the study; resulting in a final count of 20 young adults, 20 older adults with normal hearing, and 19 older adults with hearing loss who participated.Participants underwent dual-task auditory and balance testing while standing on an instrumented dual-belt treadmill. Participants were required to stand and maintain their balance with unexpected surface translations while simultaneously listening and repeating back sentences. Dual-task auditory- balance sentences were randomized to control for a learning effect –21. Part2 and no backward surface translations, resulting in the single task of listening and repeating back the sentence; “1” backward surface translations at acceleration of 2 m/s2; and “2” backward surface translations at acceleration of 5 m/s2. The surface translations induced a loss of balance requiring the participants to take 1 or more compensatory steps forward to maintain their balance. An overhead harness system equipped to support up to 181 kg was in place to prevent participants from hitting the ground if a fall would occur.Backward surface translations were delivered through the treadmill dual-belt system causing the participant to experience a forward loss of balance, while he or she simultaneously listened and repeated the sentence. Three balance conditions were delivered: “0” at 0 m/sCombinations of three auditory and three balance conditions were provided randomly and each participant completed 8 trials per combination of auditory-balance conditions.A 12 camera Motion Analysis System collected kinematic data from 54 reflective markers placed on anatomical landmarks of the body. The V-gait treadmill system by Motek Medical containing 2 separate force plates mounted underneath each belt was used to deliver surface translations and record force data .The primary outcome measures were number of steps and BKB-SIN scores. Number of steps was recorded using visual observation with Cortex Motion Analysis to verify for any uncertainties. Only 1 fall into the harness occurred during data collection; therefore, steps leading to the fall were counted. The BKB-SIN was scored by a single grader, who wore headphones connected via Bluetooth to a microphone worn by the participant.The number of steps and BKB-SIN scores across the 8 trials per combination of auditory-balance conditions were averaged by person, resulting in an average outcome score per combination. For each outcome, repeated measures ANCOVA models were run in Stata 13.1 using group, time, auditory condition, and balance condition as predictors. All independent variables were coded as categorical with the first group entered as the referent group, and time, auditory, and balance conditions designated as repeated measures variables. The between-participants error terms was designated as “ID|time”, ID was designated the variable representing the lowest unit in the between-participants error term, and time was designated as the group variable for computing the pooled covariance matrix.Baseline characteristics for the sample of 59 participants by group are presented in The results suggest that group, auditory condition and balance condition (perturbation level) are significantly related to both outcome measures. There were significant difference in the BKB-SIN score between groups, auditory and balance conditions  .There was a significant difference in number of steps between groups, (p=0.0001), auditory conditions (p=0.0301), and balance conditions (p<0.0001) . In addiThe results of this study state there are significant differences in BKB-SIN scores and number of steps between young and older adults with normal hearing, and older adults with hearing loss. These results suggest older adults with hearing loss have poorer reactive balance compared to young and older adults with normal hearing. In older adults with normal hearing, simulated hearing loss negatively affects the ability to regain balance as reflected by an increased number of steps needed after a perturbation. However, the balance performance, as measured by the number of steps required to regain balance while wearing hearings aids, may not have significantly improved enough to prevent a fall. This suggests that while, hearing aids are beneficial for speech recognition, their impact in reversing the negative effect and improve balance control is not as easily measured or understood.These results coincide with the mixed literature regarding hearing loss and balance difficulty among older adults, as well as whether hearing aids improve balance for older adults with hearing loss . Older aOne limitation to the study was the size of the treadmill and the harness system. All individuals were limited in the number and direction of steps able to be taken compared to a setting where participants are able to move more freely . AnotherIt is currently unknown how and why older adults with hearing loss fall more often compared to older adults with normal hearing . More reOlder adults with hearing loss appear to require an increased number of steps to regain balance and may be at a greater risk for falling compared to older adults with normal hearing. Number of steps may be an appropriate balance outcome measure to assess fall risk for older adults with hearing.


This study describes sound localization and speech-recognition-in-noise abilities of a cochlear-implant user with electro-acoustic stimulation (EAS) in one ear, and a hearing aid in the contralateral ear. This listener had low-frequency, up to 250 Hz, residual hearing within the normal range in both ears. The objective was to determine how hearing devices affect spatial hearing for an individual with substantial unaided low-frequency residual hearing. Sound-localization performance was assessed for three sounds with different bandpass characteristics: low center frequency (100–400 Hz), mid center frequency  and high frequency broad-band  noise. Speech recognition was assessed with the Dutch Matrix sentence test presented in noise. Tests were performed while the listener used several on-off combinations of the devices. The listener localized low-center frequency sounds well in all hearing conditions, but mid-center frequency and high frequency broadband sounds were localized well almost exclusively in the completely unaided condition . Speech recognition was best in the fully aided condition with speech presented in the front and noise presented at either side. Furthermore, there was no significant improvement in speech recognition with all devices on, compared to when the listener used her cochlear implant only. Hearing aids and cochlear implant impair high frequency spatial hearing due to improper weighing of interaural time and level difference cues. The results reinforce the notion that hearing symmetry is important for sound localization. The symmetry is perturbed by the hearing devices for higher frequencies. Speech recognition depends mainly on hearing through the cochlear implant and is not significantly improved with the added information from hearing aids. A contralateral hearing aid provides benefit when the noise is spatially separated from the speech. However, this benefit is explained by the head shadow in that ear, rather than by an ability to spatially segregate noise from speech, as sound localization was perturbed with all devices in use. Bimodal EAS listeners rely on a cochlear implant (CI) in one ear and bilateral acoustic amplification for spatial hearing in their everyday life. Normal-hearing listeners use interaural time (ITDs) and level (ILDs) differences to localize low frequency < 1,500 Hz) and high frequency  sounds in the horizontal plane, respectively. Moreover, for broadband sounds, appropriate weighing of the ITDs and ILDs enables normal-hearing listeners to localize sounds accurately and precisely , mid-frequency (MF1000 sound: bandwidth 500–1500 Hz) and high-frequency broadband  noise bursts. The residual low-frequency hearing (20 dB HL up to 250 Hz) of the listener potentially provides access to veridical ITDs, such that this listener, when unaided, might localize low-frequency sounds accurately. If, however, the ITDs are perturbed by acoustic amplification on either side, low-frequency sound-localization performance will deteriorate. For broadband sounds, sound localization is expected to depend on how the high- and low-frequency content will be weighted to form a spatial percept. Furthermore, as the higher frequencies will be audible mainly unilaterally via the CI while the lower frequencies will be audible bilaterally via the hearing aids, the devices are likely to introduce asymmetric hearing for the higher frequencies. Such asymmetry might lead to impoverished spatial hearing.We also assessed speech recognition in noise in three spatial configurations with or without the use of hearing aids. Speech always came from the front, while noise was co-located with the speech or positioned on either the implanted or the hearing-aid side. Speech recognition was also measured in the CI-only condition, for speech and noise co-located straight ahead. We hypothesize that speech understanding depends predominantly on CI-use, and much less on acoustic amplification.The listener was a female, 67 years, with a ski slope sensorineural hearing loss in both ears . In the Sound-localization experiments were carried out in a dark sound-treated room with a background noise level of <30 dB(A). In the room a spherical-shaped wire structure with a radius of 1.3 m contained 125 loudspeakers , a mid-center frequency of 1,000 Hz  and high-frequency broadband sounds .Sounds were presented from 16 speaker locations ranging from −75 to +75 in the horizontal plane in 10 steps, at a level of 65 dBA as measured at the position of the listener's head with a calibrated sound-level meter (ISO-TECH SLM 1352 P). A green fixation LED was presented straight ahead before the start of each trial. The listener had to point a red laser pointer mounted on a head-fixed spectacle frame, toward the green fixation light. The listener operated a button box to start a new trial. Pressing the button extinguished the fixation light, and triggered a 150 ms duration noise burst after a 200 ms delay. The listener was instructed to orient the head toward the perceived direction of the sound as quickly and as accurately as possible. After each goal-directed head movement, the green fixation light was presented again to start the next trial. An acquisition time of 2 s was set to record the head movements.We tested the following four listening conditions:Completely unaided, in which all devices were turned off (denoted by the symbol X), and the ear canals unoccluded.Fully aided, with acoustic (A) stimulation in the contralateral hearing aid ear and electro-acoustic (EA) stimulation in the CI ear.Electro-acoustic stimulation (EA) only with contralateral acoustic amplification (A) from the hearing aid ear taken off.Acoustic amplification (A) only with EA taken off.We analyzed the stimulus-response relations by fitting the data with the following linear relationshipr and αt are the azimuth response and stimulus locations, respectively (in degrees). The dimensionless slope, g, is referred to as the gain of the stimulus-response relationship; a gain of 1 is indicative for a perfect stimulus response relationship. The intercept, b, is the response bias in degrees, and will be zero in case of perfect localization. A positive (rightward) bias would mean that sounds tended to be localized toward the CI side, while a negative bias (leftward) would indicate perception toward the HA side. We also calculated the response variability (σr) by taking the standard deviation of the residuals between the data and the optimal regression line. We used the root mean-squared error (RMSE in degrees) across all trials to quantify the overall accuracy of the responses.where αSpeech recognition in noise was measured in the same recording session as the sound localization test. We used the Dutch Matrix sentence-in-noise test , 5 for tThree lists of 10 sentences were presented for each spatial configuration. Each sentence consisted of five words, randomly selected from a list, but arranged in a fixed grammatical order (for example a sentence translated in English: “Mark gives five large flowers”). The sentences were presented at a fixed level of 65 dB(A). The noise level was adapted according to the procedure described by  located in front and at +/−90 on either side of the listener.Each of the three lists presented per condition tracked for 50 % correct word recognition. The last four responses of each list were taken to calculate the mean speech recognition threshold (SRT) and the 95% confidence intervals of the mean was also calculated.Spatial release from masking (SRM) was calculated by taking the difference in speech recognition thresholds between S0N0 and S0NHA or S0NCI.r = 5  is shown in the second row. Again, the listener could accurately localize the LF250 sounds with all devices turned on . When thr = 10), while localization responses to HFBB noise were worse and biased toward the EA side . The improved localization for the mid-frequency noise bursts suggests that the contralateral hearing aid perturbs the sound localization cues available up to 1,500 Hz (cf. panel E vs. H).The third row of The fourth row of The speech-recognition thresholds are presented in p = 0.09) for the fully aided A – EA condition with additional acoustic amplification, in comparison to CI-only hearing X - EX The measurement for the completely unaided condition (not shown) was discontinued because the listener could not recognize the sentences. This illustrates that the cochlear implant was required for speech recognition in noise for this listener.In the CI-only listening condition X – EX in the S0N0 configuration, the signal-to-noise ratio was 3.2 ± 1.5 dB. The SRT did not significantly improve  was enhanced through electrical stimulation on the EA side . The resDorman et al.  reportedThe listener did not benefit from the acoustic devices in the speech-recognition task when speech and noise were co-located . This obThe listener had good access to localization cues in the unaided condition, which deteriorated with device use. In contrast, the benefit of the devices for the listener in recognizing speech was obvious. This finding suggests that the listener did not rely on ITDs for speech recognition in noise, and that the CI was the major, dominating source for the audibility of the speech signal.The SRM of 4.7 dB compares well to the acoustic head-shadow effect for broad-band speech signals, as reported in the literature , 13. TheWe conclude that the devices improved audibility of frequencies above 250 Hz, enabling significant improvement in speech recognition in noise. The audibility benefit also introduced ILDs, but these did not lead to a benefit in sound-localization performance. As suggested, these ILDs likely conflicted with the unperturbed ITDs, leading to an impaired sound-localization ability of the listener for all stimuli containing mid and high frequencies. Sound localization remained accurate and precise for low-frequency sounds, suggesting that acoustic and electrical amplification at higher frequencies, and the insertion of the CI electrode, did not affect ITD processing at frequencies where hearing was preserved.The bimodal EAS listener with near-normal and symmetric low-frequency residual hearing presents a rare, but interesting case. This report emphasizes the importance of hearing preservation; without low-frequency residual hearing, adequate ITD processing would not be possible, and low-frequency sound localization would probably be impaired.Remarkably, the subject reported that the devices (CI and HA) were used occasionally, only during conversations. When she was out in traffic, however, she preferred to use no device. These choices by the subject might be related to the reported outcomes of this study.Given these findings, the possibility of implanting a second EAS device should be considered for similar listeners. Bilateral EAS devices potentially provide symmetric hearing even for the higher frequencies, which potentially allow for reliable ILDs across the (restored) hearing range, and might enable spatial hearing in the aided condition as well.http://hdl.handle.net/11633/aaci5jrc.All data are available from the Donders Institute for Brain, Cognition and Behavior repository at: All experimental procedures were approved by the local Ethics Committee of the Faculty of Social Sciences of the Radboud University (protocol nr. ECSW2016-2208-41). The listener gave her full written informed consent, prior to participation in the experiment. A written informed consent was also obtained from the participant for the publication of this case report.LM, AS, AvO, and MvW contributed to the conception of the work. SS, LM, and MvW contributed to the experimental design. SS collected data. SS and MvW performed the analysis. All authors contributed to the interpretation of the data and were involved in writing the manuscript.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.


Congenital Cytomegalovirus (cCMV) is the most common cause of non-genetic hearing loss in childhood. A newborn hearing screening program (NHSP) is currently running in Italy, but no universal cCMV nor statewide hearing-targeted CMV screening programs have been implemented yet.This observational monocentric study was aimed at estimating the rate of cCMV infections identified by CMV-DNA analysis on Dried Blood Spots (DBS) samples in deaf children identified via NHSP in Northern Italy in the period spanning from 2014 to 2018.Children with a confirmed diagnosis of deafness and investigated for CMV-DNA by nucleic acid extraction and in-house polymerase-chain reaction (PCR) on stored newborns screening cards (DBS-test) were included in this study. Deafness was defined by a hearing threshold ≥20 decibel (dB HL) by Auditory Brainstem Responses (ABR); all investigated DBS samples were collected within 3 days of life.Overall, 82 children were included . Most of them (70.7%) presented bilateral hearing loss with a symmetrical pattern in 79.3% of the cases. ABR thresholds were ≥ 70 dB HL (severe/profound deafness) in 46.5% of children. Among all tested children, 6.1% resulted positive for cCMV. The rate of severe/profound deafness was statistically higher in children with cCMV infection.The addition of DBS-test to the NHSP allowed the identification, in their first months of life, of a cCMV infection in 6.1% of children who had failed NHS. The introduction of a targeted CMV screening strategy could help clinicians in the differential diagnosis and in the babies’ management. DBS samples can be considered a “universal newborns biobank”: their storage site and duration should be the subject of political decision-making. Cytomegalovirus is the leading cause of congenital infection (cCMV) affecting up to 0.8% of newborns in high income countries . A wide According to the recent literature, the virological investigations for cCMV in infants failing their newborn hearing screening program (NHSP) - which is performed in many countries- could overcome the absence of an universal cCMV screening –6.The diagnosis of cCMV infection can be achieved by the examination of salivary/urinary samples collected within the first 2–3 weeks of age as the results of NHSP ; after tThis observational single-centre study was aimed at estimating the rate of cCMV infection in children with hearing loss identified via NHSP who were referred to a Pediatric Audiology department in Lombardy  between 2014 and 2018.cCMV infection was diagnosed through the virological examination of DBS retrieved from the Regional neonatal screening centre.st 2014 and December 31th 2018.This observational monocentric study was conducted in Milan  between January 1All children belonging to the 2014–2018 birth cohort failing NHSP with transient-evoked optoacoustic emissions (TEOAE) in one or both ears and that also underwent Automated Auditory Brainstem Responses (A-ABR) were eligible in the study. Children who showed abnormal A-ABR recordings referred to the Audiology Department of the “Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico” and with an informed consent for retrieving and testing of DBS samples for cCMV diagnosis were included in the study.Data of included children encompassed gender, age, age at diagnosis of hearing loss; information on hearing loss severity, laterality and occurrence of unilateral hearing loss were also collected at the enrollment.i)with mild/moderate (20–70 dB HL) vs. severe/profound (> 70 dB HL) hearing loss according to ABR Wave threshold;ii)affected by unilateral vs. bilateral hearing loss;iii)presented with bilateral symmetric or asymmetric hearing loss pattern. When hearing loss was asymmetric, the worse ear was considered in the hearing loss level allocation.The study population was categorized according to the result of the ABR assessment:Written informed consent was obtained from the legal guardian of the children. The study was performed according to the guidelines of the Institutional Review Board on the use of biological specimens for scientific purposes in keeping with Italian law (art.13 D. Lgs 196/2003). Since this was a retrospective study on the results already available with us, it was not put up for any clearance to an ethical committee. The data were handled anonymously. The study accomplished the Helsinki Declaration of 1975, rev. 2000.Clinical ABR determination of hearing threshold was carried out at the Audiology Department at the “Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico di Milano”, a third level referral audiological centre in Milan. In brief, babies were tested under spontaneous sleep conditions in a soundproof and Faradized room; Ag-AgCl electrodes were stuck in a conventional A1-A2-Cz-Fpz configuration and connected to the Navigator Pro  recording apparatus.The stimuli were biphasic clicks delivered monaurally via a TDH-39  transducer at a repetition rate of 11pps with 10 dB HL steps of decreasing in intensity until the wave V became indistinguishable from the baseline. Responses to 2000 clicks were averaged. For each recording condition the trials were repeated at least twice.When a diagnosis of deafness was confirmed for a child, an informed consent for retrieving and testing of DBS samples for cCMV was obtained from parents.st 2014 and December 31th 2018, DBS samples collected from children with a diagnosis of deafness were retrieved from the regional neonatal screening centre and tested for CMV at the Virological Laboratories of the Department of Biomedical Sciences for Health, University of Milan.Between January 12; overall area of punches: 21.3 mm2) of DBS were collected from each ‘Guthrie’ card. The punches were initially incubated in 35 μL of Minimum Essential Medium plus Earle’s solution  overnight at 4 °C, followed by 60 min at 56 °C and then heated for 7 min at 100 °C. After 3 min of centrifugation  the supernatants were frozen for 1 h at −80 °C. An house-keeping gene was amplified with a PCR designed to recognise human beta-2 microglobulin, as previously described [DBS samples were processed by two separate in-house steps consisting of DNA extraction from the DBS samples by a heat-extraction-method, followed by amplification of a fragment of the CMV genome using a nested-PCR. Briefly, 3 × 3 mm punches .The statistical analysis was performed using the Open Source Epidemiologic Statistics for Public Health  version 3.03. The frequencies were expressed as a crude proportion with a corresponding 95% confidential interval (CI), assuming a normal distribution. Proportions between groups were compared using the Mid-P exact test based on binomial distribution. Lower (Q1) and upper (Q3) quartiles were computed. The risk of infection was expressed as the number of individuals with a laboratory-confirmed cCMV infection out of the total number of children with hearing loss and a specific characteristic. Odd Ratio (OR) and exact CI were computed. The two-sample During the 4 years recruitment period, 89 children failed NHSP. For 82 of them (92.1%) the DBS samples were available and included in the study. For 7 children DBS samples were not retrieved because stored out of our regional screening center or the informed consent was not obtained thus were excluded from the data analysis.p-value =0.08).For children included in the study, the median age for ABR diagnosis after NHSP was 3.4 months (Q1: 2 months - Q3: 5.3 months). Most hearing loss diagnoses  were achieved before the age of 6 months and more than half of them  were obtained before the age of 3 months. No differences in distribution by gender were observed: 50/82 (60.9%) were males  of cases. ABR threshold resulted ≥70 dB HL (severe/profound deafness) in 46.5% of the children . Twenty-eight out of 82 children , required hearing aids.Seventy-seven percent of children  presented with bilateral hearing loss that showed a symmetrical pattern in 79.3%  of DBS samples tested positive for cCMV. The rate of children with severe/profound deafness was significantly higher in those with cCMV infection than in the remaining others: 100% vs 42.9% respectively .No difference between unilateral and bilateral hearing loss  and between symmetrical vs. asymmetrical hearing loss  was evidenced comparing cCMV-positive and cCMV-negative children.cCMV infection is a very serious public health issue, either for its significant prevalence - up to 1% of all newborns - and for the severe and permanent sensorial and neurological impairments it can cause .Hearing loss due to cCMV infection can be already detected at birth, but a diagnosis is commonly established later on, usually during the first years of life, owing to the often delayed and progressive manifestation of the neurological damage . The besAt present, no universal- or hearing-targeted cCMV screening is operating in Italy; Tuscany is the only region where all the newborns who failed the first level screening with TEOAE are tested for urinary CMV DNA within the 15th day after birth .In our observational single-institution study, hearing loss has been diagnosed via NHSP, whereas the ascertainment of the cCMV nature of the damage was possible through the examination of DBS samples collected at birth, whose usefulness for cCMV diagnosis has been widely demonstrated , 12–15. DBS are the only samples routinely collected at birth and stored, for a short or extended time depending upon each country policies; thus, they represent a ‘universal newborns biobank’ that offers the best chance to get a retrospective cCMV diagnosis.Even though the sensitivity of DBS testing can be highly variable since it is strongly affected by the blood component release from ‘Guthrie’ Card and by the nucleic acid extraction methodology applied for –15, the p = 0.018) in children with cCMV infection (100%) than in the rest of the group (42.9%), making the risk to develop a severe/profound deafness higher in children with cCMV infection. This implies that likelihood of developing severe/profound deafness is much higher in the event of cCMV, confirming the trend observed by other researches [As far as the correlation of cCMV infection to severity and laterality of hearing loss is concerned , 16, in searches , 16.A review from Grosse et al.  showed tRegardless of hearing loss aetiology, children language outcomes depend on time of deafness’ recognition and can be improved with a diagnosis within 6 months of age , 6, 17.In conclusion, using the DBS-test based on NHSP allowed to identify cCMV infection in 6.1% of children failing NHSP in their first months of life, and to recognize that the risk to develop severe/profound deafness was higher in the event of cCMV. We are convinced that it is time to move toward a hearing-targeted CMV screening strategy, that would provide undoubted benefits for patients and clinicians . MoreoveFinally, DBS samples can be considered a “universal newborns biobank”: the site and the duration of their storage should be addressed in political decision-making. The alternative of leaving the DBS samples to parents could overcome the fear of loss of privacy and the costs for a correct samples storage.


Introduction: Hearing and vision loss are highly prevalent in elderly adults, and thus frequently occur in conjunction with cognitive impairments. Studies have shown that hearing impairment is associated with a higher risk of dementia. However, evidence concerning the association between vision loss and dementia, as well as the co-occurrence of vision and hearing loss and dementia, has been inconclusive.Objectives: To assess the association between: (i) either hearing or vision loss and the risk of dementia, as well as between; and (ii) the combination of both sensory impairments and the risk of dementia.Methods: This case-control study was based on a 5-year data set that included patients aged 65 years and older who had initially been diagnosed with dementia diseases by one of 1,203 general practitioners in Germany between January 2013 and December 2017. In total, 61,354 identified dementia cases were matched to non-dementia controls, resulting in a sample size of 122,708 individuals. Hearing loss and vision loss were identified using the ICD-10 diagnoses documented in the general practitioners’ files prior to the initial dementia diagnosis. Multivariate logistic regression models were fitted to evaluate the associations between visual and/or hearing impairment and the risk of dementia and controlled for sociodemographic and clinical variables.Results: Hearing impairment was documented in 11.2% of patients with a dementia diagnosis and 9.5% of patients without such a diagnosis. Some form of vision impairment was documented in 28.4% of patients diagnosed with dementia and 28.8% of controls. Visual impairment was not significantly associated with dementia . However, patients with hearing impairment were at a significantly higher risk of developing dementia , a finding that very likely led to the observed significant association of the combination of both visual and hearing impairments and the risk of dementia .Discussion: This analysis adds important evidence that contributes to the limited body of knowledge about the association between hearing and/or vision loss and dementia. It further demonstrates that, of the two, only hearing impairment affects patients’ cognition and thus contributes to dementia risk. Aging populations are causing a rapid increase in the number of people affected by age-associated illnesses, such as dementia diseases  ; DeutschPrevious evidence has shown that hearing impairment is associated with a decrease in cognition and a higher risk of dementia diseases. The meta-analysis of Wei et al.  aggregatIn addition, an uncorrected refractive error, for example, could also lead to neuropathological changes  the association between either hearing or vision loss and the risk of dementia separately, as well as; and (ii) the association of the additive combination of both sensory impairments—hearing and vision loss—and the risk of dementia, using a large representative sample of more than 120,000 German adults aged 65 and older and an objective measure of sensory impairment.n = 61,354 identified dementia cases were matched to non-dementia controls, resulting in a sample of 122,708 patients with or without dementia. Hearing loss and vision loss (diagnosed prior to the dementia diagnosis) were identified using the ICD-10 diagnoses documented in the general practitioners’ files. Logistic regression models were conducted to evaluate the association between visual and/or hearing impairment and dementia.This case-control study was based on a 5-year data set that included patients aged 65 years and older who had initially been diagnosed with dementia by one of 1,203 general practitioners in Germany (cases) between January 2013 and December 2017 (index date) and patients without any dementia diagnoses during this time period (controls). In total, This study was based on data from the Disease Analyzer database (IQVIA), which compiles drug prescriptions, diagnoses, and basic medical and demographic data obtained directly and in anonymous format from computer systems used in the practices of general practitioners and specialists  by one of 1,203 general practitioners in Germany between January 2013 and December 2017 . InclusiAfter applying similar inclusion criteria, dementia cases were matched to non-dementia controls by age, sex, health insurance coverage, practice, index year (year of dementia diagnosis), and comorbidities , intracranial injury, epilepsy, Parkinson’s disease, and depression). For the controls, the index date was that of a randomly selected visit between January 2013 and December 2017 . OverallThe main outcomes of the study were the associations between objective hearing and visual impairment and dementia. As described above, the following ICD-10 diagnoses received on the index date were used to identify patients with dementia: F01, F03, G30, and F06.7. In order to identify patients with hearing impairment prior to the initial dementia diagnosis, as well as categorize hearing impairment, one of the following two diagnoses documented by general practitioners was used: conductive and sensorineural hearing loss (ICD-10 diagnosis: H90) or other hearing loss (H91). To identify patients with visual impairment prior to the dementia diagnosis, one or more of the following diagnoses were used: disorders of lens (H25–H28), disorders of choroid and retina (H30–H36), glaucoma (H40–H42), disorders of vitreous body and globe (H43–H45), disorders of optic nerve and visual pathways (H46–H48), disorders of ocular muscles, binocular movement, accommodation and refraction (H49–H52), visual disturbances (H53), and visual impairment including blindness (H54).Furthermore, socio-demographic data, including age, sex, health insurance coverage, and co-existing morbidities documented prior to the dementia diagnosis, such as diabetes mellitus (E10–14), ischemic heart disease (I20–I25), stroke including TIA , intracranial injury (S06), epilepsy , Parkinson’s disease , and depression  were assessed.To validate the matching procedure, differences in the sample characteristics between those with and those without a dementia diagnosis were tested by using chi-squared tests for categorical variables and Wilcoxon tests for continuous variables. Multivariate logistic regression models were used to evaluate the association between visual and hearing impairment and dementia incidence. The association between any or a specific visual or hearing impairment diagnosis and the risk of dementia were evaluated separately. That means that, for each hearing or vision impairment diagnosis, a separate model was used to test the association between each specific or any impairment and dementia incidence. In addition, to evaluate the association between hearing and vision loss and dementia incidence compared to healthy controls without vision or hearing impairment, patients were classified into one of the following four groups: only hearing impairment, only visual impairment, both hearing, and visual impairment, and no hearing and no visual impairment (reference group). All models were adjusted for age, sex, health insurance coverage, and the following comorbidities: diabetes mellitus, ischemic heart disease, stroke, intracranial injury, epilepsy, Parkinson’s disease, and depression. Analyses were carried out using SAS version 9.4.German law allows for the use of anonymous electronic medical records for research purposes under certain conditions. According to German legislation, it is not necessary to obtain informed consent from patients or approval from a medical ethics committee for this type of observational study, which contains no directly identifiable data. Therefore, no protected health information was available for queries and no Institutional Review Board (IRB) approval was required for the use of this database or the completion of this study.Patients were on average 81 years old, the majority were female (61%), and more than one-third were suffering from diabetes (41%), ischemic heart disease (39%), or depression (32%). The matching procedure successfully resulted in non-significant differences in socio-demographic and clinical variables between patients with dementia diseases and non-dementia controls. A description of the sample is given in Vision impairment (of any type) was documented in 28.4% of patients later diagnosed with dementia compared to 28.8% of controls. Disorders of the lens (12.6% vs. 12.7%) and visual disturbances were documented most frequently (9.3% vs. 9.2%). However, vision loss was nearly equally prevalent in patients with dementia and those without dementia, without any detectable trend favoring one of these groups.The presence of hearing impairment exclusively, without any vision impairment, was detected in 5.7% of patients with and 4.5% without dementia. By contrast, vision impairment exclusively, without any hearing impairment, was found more often in non-dementia controls (23.9%) compared to patients later diagnosed with dementia (22.9%). A combination of both hearing and vision impairment was found in 5.5% of patients with and 4.9% of patients without dementia.p < 0.001) as well as each separate hearing impairment diagnosis, such as conductive and sensorineural hearing loss  and other hearing loss  were significantly associated with an increased risk of dementia. No association was observed between any  or a specific visual impairment diagnosis and dementia.Any hearing impairment . However, the risk of developing dementia diseases was lower compared to the group of patients who had hearing impairment exclusively . Therefore, visual impairment alone was not significantly associated with dementia  compared to the reference group of patients without any hearing and visual impairment. In addition, the combination of both hearing and visual impairments was significantly associated with a higher risk of dementia  of patients in the sample were diagnosed with dementia diseases, which is well below the general population estimates for a group of the same age composition. Furthermore, the observed association was based on a much smaller sample size when compared to this analysis (Matthews et al., However, there is some evidence suggesting that vision loss is associated with an increased risk of developing dementia diseases. Based on a retrospective cohort study that included 7,685 patients, Davies-Kershaw et al.  revealedEven though dementia diseases are, in fact, underdiagnosed, the low number of dementia cases in this study limits the generalizability of these findings. Furthermore, even though some studies confirmed the comparability and validity of subjective and objective measures of vision impairment (Whillans and Nazroo, The results of our study demonstrated that only hearing loss is associated with a higher risk of dementia diseases and that the combination of both hearing and vision loss certainly increases sensory impairment, but not the risk of developing dementia diseases, thus demonstrating the importance of hearing ability as a protective factor against dementia patients. People with hearing loss have various neuronal changes. Hearing loss in older adults may result in an acceleration of aging because the nervous systems can alter synapses and neural anatomy (Martini et al., Even though the prevalence of hearing loss in patients living with dementia is very high and the association between hearing loss and cognitive decline is well studied, the utilization of hearing aids is only moderate (Nirmalasari et al., We conducted a case-control study of patients with and without a diagnosis of a dementia disease, using data from GP practices. The diagnoses listed in the files of the general practitioners are usually used for reimbursement. Therefore, the data may not be complete, especially not for vision impairment diagnoses, which are, in most cases, not documented in general practitioners’ files. Among the elderly, the prevalence of vision impairment is approximately 70%. In this study, diagnoses related to vision impairment of any type was only documented in 28% of cases, demonstrating that vision impairment was underdiagnosed and underrepresented in this data set. This limits the generalizability of the non-significant association found between dementia and vision impairment and should, therefore, be evaluated in further research, using other objective or subjective measures.Furthermore, hearing impairment during the cognitive assessment or dementia screening procedures might anticipate the dementia diagnoses due to the fact that patients are unable to hear and, thus, to understand questions included in the assessment correctly, even though these patients might not be cognitively impaired. This could lead to false-positive dementia diagnoses and, thus, could support the association between hearing loss and dementia. In addition, our analyses were based on the initially documented dementia diagnoses. It should be noted that the basic process for recognizing cognitive impairment is completely different compared to the process used for reimbursement purposes. Therefore, the diagnoses used in the analyses are not verified for their correctness and accuracy. This also applies to the diagnosis of hearing and vision loss. In addition, dementia diseases are underdiagnosed by general practitioners. In Germany, only 40% of PwD are formally diagnosed with dementia. This diagnosis rate of dementia in German primary care is well within the range of the international data (20%–50%; Eichler et al., Despite these limitations, the strength of the present study was that the analysis was based on a total of 122,708 patients treated by their general practitioners. Therefore, the sample is adequate for answering the research questions, with considerable external validity.The datasets generated for this study are available on request to the corresponding author.BM drafted the manuscript. KK is responsible for the statistical analyses. WH contributed significantly to the manuscript.KK is an employee of IQVIA and has no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.The remaining 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.