Introduction: Newborn hearing screening is essential for early identification of hearing loss to decrease the adverse effects of hearing loss. The objective of this study was to determine the prevalence of hearing loss and risk factors of congenital hearing loss in newborns.Methods: In this analytical case-control study, a hearing screening test was performed for all newborns aged 3-14 days.P=0.001), hospitalization in the neonatal intensive care unit (NICU) (P=0.008), exposure to ototoxic drugs (P=0.001), gestational diabetes P=0.01), craniofacial anomalies (P=0.01), convulsion (P=0.03), consanguineous marriage of parents (P=0.001), low birth weight (P=0.01), and hyperbilirubinemia (P=0.001).Results: Of 5,500 newborns evaluated, 24 newborns had hearing loss. The prevalence of hearing loss was 4.36 per 1,000. Of 24 hearing-impaired newborns, 15 had bilateral hearing loss (BHL) (62.5%) and nine had unilateral hearing loss (UHL) (37.5%). Among the neonates with hearing loss, the prevalence of hearing loss was higher (77.8%) in the right ear. The main risk factors identified in this study were low gestational age , gestational diabetes, craniofacial anomalies, convulsion, consanguineous marriage of parents, low birth weight, and hyperbilirubinemia were significant risk factors for congenital hearing loss in studied newborns. Hearing loss is one of the most prevalent sensory impairments in the world , with 34In the United States, it is estimated that bilateral hearing loss (BHL) occurs in one to two per 1,000 live births , and uniIt was also shown that newborns had larger transient otoacoustic emissions (TEOAEs)  in the left ear and larger distortion product otoacoustic emissions (DPOAEs)  in the right ear . These fSeveral studies have shown a number of risk factors for congenital hearing loss, including birth weight less than 1,250 grams, prematurity, hypoxia, Apgar score less than three and six in 1 and 5 minutes, respectively, seizures, ventilation, meningitis, jaundice, asphyxia, hypoglycemia, and treatment with aminoglycosides and furosemide. However, there are some newborns with hearing loss and without any known risk factors -11. TherEarly intervention for neonates with congenital hearing loss requires early diagnosis and a suitable intervention within six months of birth. Evidence shows that hearing loss is the second most common disability in Iran . There iStudy designThis cross-sectional, case-control study was approved by the Ethics Deputy of Ahvaz Jundishapur University of Medical Sciences (IR.AJUMS.REC.1399.859) and carried out in accordance with the Declaration of Helsinki. All evaluated newborns were born in the north of Khuzestan Province, Iran, and admitted to the central health center in this area.Exclusion criteriaNewborns with atresia or stenosis of one or both external ear canals and those without parental consent were excluded.Study procedureAt first, a questionnaire was completed for all newborns, aged three to 14 days. A professional audiologist conducted hearing screening tests and filled the questionnaire (appendix). The collected data included demographic characteristics, family history of hearing loss, gestational diabetes, neonatal convulsion, hyperbilirubinemia, NICU stay, duration of hospitalization, craniofacial anomalies, newborn or mother's treatment with ototoxic drugs during intrauterine growth time or after birth , parents’ consanguineous marriage, low birth weight , and gestational age <35 weeks.After giving verbal information about the hearing screening process to the parents, the informed consent forms were obtained from the parents before the hearing screening was carried out. All neonates were tested in a quiet room and the order of hearing tests was as below:1. Otoscopy for checking the bilateral external auditory canals.2. TEOAEs by Madsen Accuscreen : The intensity of click stimulation in the device was set to 35 dBnHL, and disposable ear tips were used to cover the probes during the test. When the test was done and there was an otoacoustic emission (OAE) response, the results were displayed as "PASS"  on the screen and if there was no response to a stimulus, as "REFER.”3. Automated auditory brainstem response (AABR) tests by Madsen Accuscreen : The negative electrode was placed on the ipsilateral mastoid, the positive electrode was placed on the upper part of the forehead and the common electrode was placed at the contralateral mastoid. The impedance level was kept between 1 and 5 kΩ for the electrodes. Click stimuli at 35 dBnHL, with alternating polarity and presentation rate of 37.7/s, were used. No sedatives were used for this test.Newborns who had abnormal results in one of the tests or one of the ears were reported as refer. Newborns with refer results were tested after two weeks as below:1. Neonates were checked by a tympanometer with a high-frequency probe tone (1000 Hz) .2. Diagnostic auditory brainstem response (ABR) was performed by click stimuli and presentation rate of 21.1/s with rarefaction polarity . Wave V was traced for determining the auditory threshold.3. Auditory steady-state response (ASSR) was performed for determining the degree of hearing loss . This test was performed for octave frequencies from 500 to 4,000 Hz simultaneously for both ears.As this study was a case-control study, the neonates with refer result, considered case group and a matched sex neonate from those who passed the screening stage, considered the control group. To reduce the selection bias of case-control, we used random methods when selecting neonates from populations. So, the selection was done by a staff of the central health center.Statistical analysisData were analyzed using SPSS version 16 . Mann-Whitney U test was performed for non-parametric variables, such as gender, gestational diabetes, craniofacial anomalies, NICU stay, use of ototoxic drugs, convulsion, and hyperbilirubinemia. The Student’s t-test was applied for parametric variables, including birth weight and gestational age. A P-value less than 0.05 was considered statistically significant.A total of 5,500 newborns were screened in this study, including 2,970 (54%) males and 2,530 (46%) females. Of these, 190 (3.45%) infants failed in the screening and entered into the next stage. These infants selected as the case group and including 106 (55.8%) males and 84 (44.2%) females. From 5,310 newborns who passed the test, 190 matched sex newborns were randomly selected as the control group.ABR test was carried out in the case group; 24 of whom were found to have a hearing loss. Given that the total number of newborns examined in this study was 5,500, the prevalence of hearing loss was 4.36 per 1,000 newborns.Of 24 hearing-impaired newborns, 15 had BHL (62.5%) and nine had UHL (37.5%). Among the neonates with ULH hearing loss, the prevalence of hearing loss in the right ear was higher (77.8 %) than in the left ear (22.2%). The frequency distribution of severity of hearing loss was shown in Table A significant difference between the case and control group was seen in the risk factors that were studied Table .In this cross-sectional case-control study, we investigated the prevalence of hearing loss, risk factors, and the degree of hearing loss in newborns of north of Khuzestan in a 12-month period. We found that the prevalence of hearing loss was 4.36 per 1000 live births, which is consistent with the findings of Firouzbakht et al.  and ArjmThe results of the present study demonstrated that the prevalence of hearing loss was higher in the right ear than the left ear. Consistent with our findings, Lieu et al. also reported that hearing loss in the right ear is more common than the left ear . Misic eAnother interesting finding in this study is the significant relationship between the use of ototoxic drugs and the higher occurrence of UHL. This finding is similar to Hirose et al.’s study that found medications, such as antibiotics and chemotherapy agents, could cause pediatric UHL. They mentioned that, although the causes of UHL are not well-known, the toxic effects of aminoglycoside antibiotics on cochlear hair cells have been identified as a risk factor . HoweverIn the present study, the effects of environmental and demographic risk factors on hearing loss were also examined. Our findings revealed a significant association between low gestational age (<35 weeks) and hearing loss. In other studies also gestational age below 36 weeks has been considered as a risk factor for hearing loss . UnderdeWe also found a significant correlation between low birth weight and hearing loss in newborns. It was reported that newborns with low birth weight had a high risk of hearing loss, so routine audiological assessments were recommended in these newborns. Although very low birth weight may not strongly influence the auditory system, it is usually associated with other risk factors, which can affect hearing synergistically. Therefore, the risk of hearing loss is significantly higher in newborns with low birth weight compared to the general population of newborns .Another risk factor of hearing loss which is significantly different between the two studied groups was consanguineous marriage of parents. Lotfi et al. reported that in 45.7% of Iranian children with hearing loss, there was a history of consanguineous marriage of parents . A reviePositive family history of hearing loss was another risk factor identified in the current study. The results of our study showed that the prevalence of hearing loss among families with a positive history of hearing loss was 13 per 1000 live births, which is probably due to the high rate of consanguineous marriage among people in the north of Khuzestan Province. However, a study in Turkey found that a family history of hearing loss is not a risk factor for ear anomalies in neonates . The conThe presence of craniofacial anomalies was different between the case and control groups, and a significant relationship was found between these anomalies and hearing loss which is similar to other studies which reported that the anomalies are associated with hearing loss , 11. AnoThe present findings of this study also found that the newborns of mothers with gestational diabetes were at a higher risk of hearing loss. Padmadasan and his colleagues reported the prevalence of deafness in neonates of mothers with diabetes mellitus was 7 times higher than the prevalence of this loss in neonates without any risk factor . HoweverFurthermore, hospitalization in NICU for more than five days was another risk factor, significantly correlated with hearing loss. This finding is in agreement with some previous research , 10. BieABR and OAE tests are valuable screening tests, as they can be implemented within a short period after birth. However, it is important to notice that the results of OAE test can be influenced by the outer and middle ears, producing false-positive results. Some conditions, such as auditory neuropathy spectrum disorders (ANSDs) and inner hair cell dysfunctions, cannot be detected by OAE tests too; and false-negative results may be obtained . AutomatThis study has some implications for policymakers and clinicians. Firstly, the prevalence of hearing loss is still high so developing effective interventions to address the risk factors and prevent hearing loss in newborns is necessary. The interventions could be raising awareness of clinicians and expectant mothers and about potential risk factors of hearing loss by social media and educational programs. Second, clinicians should be trained to avoid prescribing ototoxic drugs for newborns if possible and inform parents about the potential risks of ototoxic drugs for their children.The prevalence of hearing loss in the current study was 4.36 per 1,000 newborns, which is consistent with the previous studies. We also found that the prevalence of hearing loss in the right ear was higher than in the left ear, which is an important finding as it can help us determine whether children with right ear hearing loss should receive different interventions or not. But further investigation is required to determine this.NICU stay, use of ototoxic drugs, low gestational age (<35 weeks), gestational diabetes, craniofacial anomalies, convulsion, the consanguineous marriage of parents, low birth weight, and hyperbilirubinemia were significant risk factors for congenital hearing loss in our study population. It can be concluded that the use of TEOAE and AABR tests simultaneously is essential for the best diagnosis of congenital hearing losses. Therefore, timely detection and consider all risk factors of congenital hearing loss for appropriate next interventions is highly recommended.


Numerous endeavors have been undertaken to preserve hearing in cochlear implant (CI) patients. Particularly, optimization of electrode array design aims at preservation of residual hearing (RH). This study examines whether a slim perimodiolar (PM) electrode array could bear the capability to preserve hearing.n = 17), while all others belonged to the noRH group (n = 30). (ii) Another group implanted with a slim straight, lateral wall (LW) electrode was recruited for comparison.A total of 47 patients underwent cochlear implantation receiving the PM electrode. (i) Patients with pure tone audiogram (PTA) thresholds better than 85 dB and/or hearing loss for Freiburg speech test numbers less than 60 dB and more than 50% maximum monosyllabic understanding were assigned to the RH group  groups in NRT thresholds, Freiburg speech test and A§EThe results suggest that hearing preservation is influenced not only by electrode shape but various factors. This study opens an avenue for further investigations to elucidate and enumerate the causes for progressive hearing loss.The online version contains supplementary material available at 10.1007/s00405-021-06755-z. Cochlear implantation is an effective treatment option for profound sensorineural hearing loss. Compared to the first cochlear implants in the 1980′s, surgical techniques and implant technologies have evolved over the past decades . In geneHowever, to date there is no consensus about which factors are critical for hearing preservation. Some subjects eventually lose their residual hearing in long term –13. AlsoA slim, precurved modiolar electrode has been reported having combined advantages over previous cochlear implants by its precurved design, flexible-thin character and is supposedly beneficial for HP in particular.Thus, the main objective of this study is to evaluate the possibility of hearing preservation within PM recipients. To address this objective we compared (i) the PM recipients with residual hearing (RH) prior to implantation directly to patients with noRH, and additionally (ii) the PM recipients to LW recipients to examine the role of electrode shape in hearing preservation. As the PM electrode is thinner than the LW electrode and precurved, our study hypothesis is that PM recipients might show better hearing preservation in adults.®/PM electrode) at our department of Otorhinolaryngology between 9/2016 and 11/2018 after informed consent. The study was approved by the local ethics committee and was conducted in accordance to the Declaration of Helsinki. The inclusion criteria were defined as following: firstly, minimum age of 18 years at implantation. Secondly, native German language skills were required  to answer the questionnaires as well as for participating in Freiburg speech test. Depending on the level of residual hearing prior to implantation subjects were split into 2 groups: 17 patients with residual hearing (RH) and 30 patients without residual hearing (noRH). RH was defined according to the following criteria: (i) hearing threshold better than ( <) 85 dB for pure tone audiogram (PTA) frequencies 250–500–1000–2000 Hz, and/or (ii) hearing loss for Freiburg speech test numbers of less than 60 dB and more than 50% of maximum Freiburg monosyllables understanding (40 items each). All study participants gave written informed consent prior to study inclusion. For comparison, data from 26 patients with a Slim Straight electrode  were compared to the PM recipients. Patients who were unable to attend their regular check-up appointments either because of missing, declining or postponing their appointments or relocating post-implantation were summarized as “loss of follow up”.All 47 subjects received the Nucleus Slim Modiolar Electrode  The CI532 implant is precurved and secured in a thin sheath to hold it in straight position aiming at perimodiolar position. Due to the greater diameter of the insertion tool in all cases, it required an extended round window or a combined (round window/cochleostomy) approach. (ii) The CI522 implant consists of a slim straight electrode aiming at a lateral wall position. All CI522 electrodes could be inserted by a round window approach, as there is no additional insertion tool.The NucleusBoth electrodes were inserted into the cochlea by slowly advancing the electrode until the white markers were aligned. For the CI532 insertion, the sheath is pulled back by its grip and the three markers of the electrode were kept in position in the cochlear opening. Intraoperatively all subjects received 250 mg prednisolone intravenously shortly before insertion.LEL) and lateral wall length (LLW) (WF = LEL/LLW). The smaller the WF value becomes, the closer the electrode is aligned to the modiolus of the cochlea (LEL < LLW). WF values of the PM electrode were related to the LW electrode.To ensure the correct position of the electrode ConeBeam, Computed Tomography (CT) (intraoperatively) or regular CT scan (postoperatively directly after surgery) was conducted. Electrode position was evaluated to determine the Wrapping factor (WF) according to Holden et al. . WF is cResidual hearing levels were compared by unaided pure-tone audiometry (PTA). Hearing thresholds were detected for different frequencies by bone and air conduction (250–500–1000–2000 Hz) before surgery, on the first day, 3–6–12 months post-surgery in a regular follow-up setting. Particularly, bone conduction thresholds were compared to analyze inner ear functions. Bone conduction values on the first day post-surgery were inconsistent due to different setups and bandages, hence these values were neglected for further analysis. If no detectable threshold for the tested frequency was observed, hearing threshold was visualized as > 110 dB in the PTA graphs.Objective audiometry was measured as electrically evoked compound action potentials (ECAPs) in neural response telemetry (NRT) as reported previously . BrieflyFreiburg speech recognition was tested for 50% recognition level of numbers and maximum of monosyllabic words at 65 dB as first described by Hahlbrock et al. . The imp®, developed by The Eargroup , was assessed to compare speech sounds in best aided conditions before cochlear implantation and during follow-up. Best aided condition was attained by wearing hearing aids and/or CIs during the hearing test. The hearing aids were validated and optimized prior to cochlear implantation by an experienced hearing care professional. In general, A§E® is a useful tool for frequency-dependent fitting in cochlear implant patients that is more independent from age, cognitive level and language skills than other speech tests  [A§Ech test) . Speech Subjects were asked to complete the questionnaires “HISQUI19” and Oldenburg Inventory prior to the implantation, 3, 6 and 12 months after implantation.®) was applied. The subjects filled out a form containing 19 questions. Each of the question had a score ranging from 1 (never) − 7 . Upon aggregation, the scores were categorized into: < 31: very bad sound quality, 31–60: bad sound quality, 61–90: medium sound quality, 91–110: good sound quality, 111–133: very good sound quality.To evaluate the subjective sound quality in patients, the questionnaire ‘Hearing Implant Sound Quality Index’  is a questionnaire requiring patients’ evaluation on subjective abilities to hear in daily life with hearing aids/implants. Patients were asked to gauge their understanding  for the situation at home, work and while interacting with others. Each question  represents a certain hearing condition in silence, noise and direction. For the statistical analysis, scores ranging between 1 and 5 were distributed for each condition and related to the maximum score (= 100%).p values below 0.05 were considered to be significant.Data analysis was performed using GraphPad Prism 7 for Mann–Whitney test. Patients’ clinical characteristics are summarized in Table The LW recipients were matched for age and gender: 19 patients belonged to the RH group and 7 patients to the noRH group according to the above defined criteria. Most patients (92%) suffered from symmetric hearing loss and presbyacusis/idiopathic hearing loss. 18 CIs were implanted in the left ear and eight CIs in the right ear.CT scan images showed a proper localization of the PM electrode in the scala tympani of the cochlea in almost all cases Fig. a. In twoBone-conduction PTA levels in PM-implanted patients rapidly adjusted to noRH values (> 110 dB) in the course of the first 6-month follow-up: PTA averages prior to implantation. After 12 months, none of the implanted patients showed RH anymore  NRT values showed after an initial decrease at 3-month follow-up stable CL without significant differences between RH and noRH patients in the follow-up period .Oldenburg Inventory (OI) showed comparable average satisfaction after cochlear implantation in both groups in the first year with slightly higher satisfaction rates in favor of the noRH group. Overall, patients in best aided condition indicated high satisfaction rates of hearing in silence (> 75%) , whereas hearing in noise and directional hearing reached lower satisfaction rates of 60–75% in both groups . As an internal control for OI, questions addressing hearing without any hearing aid (wo HA) were included in the questionnaires and patients indicated the same levels (< 25%) as prior to implantation .This study aims at (i) evaluating HP in PM recipients with RH and (ii) in context of the implanted electrode design of the PM electrode compared to the straight LW electrode. The results indicate that HP is more favorable with the LW electrode than PM electrode. Especially, bone-conducted PTA revealed that all PM recipients lost their RH, whereas approximately 25% LW patients had well-preserved low frequency hearing (250–500 Hz) 1 year after implantation. Overall, HP in PM electrodes has been controversially discussed in the literature. Other investigations demonstrated identical results for both PM and LW electrode groups, and, at 6-month or 1-year follow-up , 21. HowThe comparatively better RH levels of LW electrodes are ascribed to the thin and flexible electrode array, which results in less insertion damage. Hence, less neuron damage, fibrosis induction and bone-development is induced , 14. PreLately, the monitoring of intracochlear electrocochleographic amplitudes during cochlear implantation has been demonstrated to be beneficial for HP , 28.The Auto tNRT results of the PM group support this hypothesis: Current levels for basal regions are higher than medial or apical regions and do not show significant differences between the RH and noRH group Fig. b. AlthouTip fold over was observed in 2 of 47 cases in the PM patients (4.2%) and none in the LW patient group. The tip fold over rate with the PM electrode in this study is roughly two times higher than the tip fold over rate with other electrodes, consistent with a larger case study of 235 CI patients by Friedmann et al. and others , 32, 33.® detection and discrimination showed no significant distinction among both groups  all PM recipients with RH lost their residual hearing within 1 year and (ii) the electrode design had an impact on HP.Supplementary Figure 1. PM patients rated their (A) overall sound quality in HISQUI19 and (B) hearing impression in certain daily situations  in Oldenburg Inventory (OI). (A) noRH patients rated better overall sound quality than RH patients during the initial fittings. Rates equalized at the first-year follow-up (p>0.05). (B) OI-Hearing in silence was high (75-100%) and over 12 months stable ranked in both PM/RH and PM/noRH. (C) Hearing in noise and (D) directional hearing was consistently medium ranked in both groups (p>0.05). Ranking values without any hearing aid reached very low rates as expected and comparable to the rankings prior to implantationBelow is the link to the electronic supplementary material.


This review focuses on peripheral forms of hereditary hearing loss and how these impairments can be studied in diverse animal models or patient-derived cells with the ultimate goal of using the knowledge gained to understand the underlying biology and treat hearing loss.Inherited forms of deafness account for a sizable portion of hearing loss among children and adult populations. Many patients with sensorineural deficits have pathological manifestations in the peripheral auditory system, the inner ear. Within the hearing organ, the cochlea, most of the genetic forms of hearing loss involve defects in sensory detection and to some extent, signaling to the brain  Impairment of hearing can be due to several factors including environmental insults, the effects of aging, and hereditary defects. Of these three forms, the most common form is due to aging , which c1 Of the non-syndromic forms, more than 120 genes have been implicated in hearing loss and the majority of cases involve recessive mutations in which both copies of the gene are mutated. Approximately a third of the cases are dominant, requiring only one copy to be mutated. As with aging, sometimes the middle ear is affected, leading to a loss of conduction of sound. However, the majority of mutations are sensorineural in nature, mainly affecting the inner ear, with many having developmental or functional consequences for hair cells.Hereditary hearing loss is one of the most common sensory deficits in humans affecting one out every 500 newborns . The levEfforts to understand the etiologies associated with hearing loss have been ongoing for several decades. The purpose of this review is to highlight a few recent studies of non-syndromic hereditary hearing loss that illustrate the different types of pathology found in the inner ear. The following studies focus on three different tissue or cell types of the cochlea, namely the stria vascularis, sensory epithelium and the afferent neurons of the spiral ganglion. These studies were also chosen based on the variety of animal models or the use of human-derived cell lines to determine the function of the genes. Due to the inaccessibility of the inner ear in patients, a basic scientific approach with models is necessary to gain a better understanding of the nature of the defects caused by genetic variants that are associated with human hearing loss.An important prerequisite for hair-cell function is the presence of an ionic environment that is conducive to excitation. Unlike other extracellular fluids throughout the body, the fluid inside the scala media of the inner ear is exceedingly rich in potassium ions . The higAlthough marginal or “dark” cells found in the vestibular inner ear of vertebrates are thought to perform a similar function to the stria vascularis, the electrochemical potential created is substantially lower and defined cell layers are not evident . FurtherHGF). Despite the name suggesting a specific role in the liver, this extracellular ligand has been implicated in many biological processes involving cell proliferation, survival, and motility. More surprisingly, the only disease in humans associated with mutations in HGF is non-syndromic hearing loss. In mice, the knock-out of Hgf results in embryonic lethality, whereas a conditional knock-out in the inner ear does indeed result in deafness . Zebrafish have an inner ear that is anatomically similar to the vestibular portion of human ears. For hearing, they use the saccular end-organ. The sensory hair cells in the zebrafish inner ear rely on many of the same basic components necessary for hearing and balance in humans, and well over a dozen models of human hearing loss have been generated and studied in detail [for comprehensive reviews of studies in zebrafish see As an illustration of (i) using a non-rodent model, the zebrafish, to study human hearing loss, and (ii) the ability to compare the findings with this animal model to that of the mouse model, this review will focus on two recent studies of transmembrane inner ear  play a more critical role in hearing  projecting out of the bone-encased inner ear into the hindbrain. The fibers of the afferent neurons in the cochlea along with the cell bodies comprising the spiral ganglion are shown in yellow in DIAPH1, TMPRSS3 and PJVK  and the vertebrate inner ear. Of the genes required for auditory function in fruit flies, 20% have human orthologs implicated in deafness  in the antenna harboring the Johnston’s organ caused deficits in gravity sensing and balance in adult flies. At the cellular level, the sensory scolopidia were disorganized, including abnormalities of internal structures such as actin bundles, and there was a loss of synapses formed by scolopidia neurons in the fly brain. To test the whether the Gln104Leu variant was causative, the authors compared rescue of the behavioral defects in the drk fly mutant by expressing the wild type human gene and the human Q104L variant and found that the variant form of GRAP was ineffective at rescuing the fly phenotype. The ability to rescue the deficits of an animal model with the corresponding human gene and test newly identified variants is an important and much needed approach for establishing causality of mutations found in the genome of hearing loss patients.A recent study of a novel deafness gene serves as an excellent example of the use of flies to study hereditary hearing loss . In thisin vitro experiments. The authors found that sensory neural-like cells heterozygous for the S1400G mutation had defects in later steps of differentiation and physiological responses. These defects were accompanied by a decrease in microtubule dynamics. Most of the heterozygous S1400G cells had shorter neurites in contrast to the CRISPR-corrected cells or sibling-derived cells. To further confirm their findings, the authors engineered a mouse model expressing the same dominant mutation. Heterozygous mutant mice displayed moderate yet progressive hearing loss. In addition, primary cultures of the spiral ganglion neurons exhibited similar decreases in neurite length and altered electrophysiological properties.The study of animal models is invaluable for understanding the potential etiology caused by mutations. Nevertheless, with the recent advances in stem cell biology, it is also possible to take cells from patients such as blood cells and reprogram them into cells that resemble those in the auditory system. in vitro studies. This approach is an invaluable method for assessing the pathological consequences of a mutation in human cells. Although the technology is in its infancy, another potentially useful method is to generate human organoids of the inner ear. These 3D structures contain cell types that resemble hair cells and the sensory neurons that innervate them (The above study highlights the utility of reprogramming patient-derived cells into a desired cell type for ate them . Inner evia genomic sequencing and to establish animal models or study patient derived cells is a key step toward selecting the appropriate therapeutic approaches to ameliorate hearing loss.In summary, hereditary sensorineural forms of hearing loss primarily affect the tissues and cell types of the inner ear that are vital to sensing sound and transmitting signals to the brain. Our knowledge of the genetics of hearing loss is growing as the pace of identifying novel human mutations associated with impairments in hearing is rapidly increasing . This inDrosophila are highly advanced, the existence of an obvious ortholog of a human deafness gene is not always the case. In addition, extrapolating the pathological defects in fly mutants to potential defects in human patients can be challenging due to the very different structures of the hearing organs in flies. With respect to zebrafish, some deafness genes may be duplicated due to the large-scale duplication of approximately 40% of the genome in teleost fish during evolution. Depending on the expression pattern of the gene duplicates, it may be necessary knock out and analyze two genes instead of one. Also, fish do not have a cochlea; questions about the structures or tissues present only in the mammalian cochlea cannot be addressed. In mice, the need for dissection and cochlear explants to study the cellular defects makes the work more challenging. Generally, research with this particular animal model tends to be more costly and time consuming. Branching out to the use of human stem cells and organoids to study hearing loss is certainly exciting and gaining traction. Whether in vitro differentiated cells truly resemble desired cell types or how well the organoids recapitulate the environment of the inner ear is, however, not clear. To date, generating auditory hair cells from stem cells has yet to be achieved. Despite the above shortcomings, animal and cell models have been very valuable for studies of human hearing loss and continuing efforts with these models will undoubtedly yield more insights into the defects and pathology at the molecular, cellular and physiological level.The choice of animal or cell model is dictated by several factors. Although the genetic methods in Aside from helping patients navigate hearing loss, research with animal models and patient-derived cells increases our basic understanding of how the inner ear works. These studies also add fascinating insights of how this remarkable sensory organ evolved and they provide clues about strategies that are employed to suit the auditory needs of a particular animal. On the whole, the interplay between basic and translational research is a fruitful one and offers hope to patients with hearing loss.The author wrote the manuscript and confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The aim of the study was to compare long-term results after 1 year in patients with single-sided deafness (SSD) who were fitted with different hearing aids. The participants tested contralateral routing of signals (CROS) hearing aids and bone-anchored hearing systems (BAHS). They were also informed about the possibility of a cochlear implant (CI) and chose one of the three devices. We also investigated which factors influenced the choice of device.Prospective study with 89 SSD participants who were divided into three groups by choosing BAHS, CROS, or CI. All participants received test batteries with both objective hearing tests  and subjective questionnaires.16 participants opted for BAHS-, 13 for CROS- and 30 for CI-treatment. The greater the subjective impairment caused by SSD, the more likely patients were to opt for surgical treatment (BAHS or CI). The best results in terms of speech perception in noise , sound localization, and subjective results were achieved with CI.The best results regarding the therapy of SSD are achieved with a CI, followed by BAHS. This was evident both in objective tests and in the subjective questionnaires. Nevertheless, an individual decision is required in each case as to which SSD therapy option is best for the patient. Above all, the patient's subjective impairment and expectations should be included in the decision-making process. People who suffer from single-sided deafness (SSD) have difficulty understanding speech, especially when the sound comes to the deaf ear or in noise, as well as in the localization of sounds . PatientIn this prospective study, 89 adult (age > 18 years) patients with SSD were included. The study was conducted in accordance with the recommendations of the Ethics Committee of the University of Freiburg, Germany (protocol numbers 175/08 and 69/09) and in accordance with the Declaration of Helsinki (2013). The audiological classification of SSD was: untreated hearing ability of the poorer-hearing ear with a mean bone-conduction audiometric threshold for the frequencies 500, 1000, 2000, 4000 Hz  greater than or equal to 70 dB hearing level (HL) and an air-conduction 4PTA of less than or equal to 30 dB HL for the better-hearing ear [After signed informed consent was obtained, an audiological assessment was performed in all participants at baseline including the following measures: pure-tone hearing thresholds, speech intelligibility for Freiburg monosyllables and numbers, tympanograms, and auditory brainstem responses (ABR). In participants who decided for a CI, transtympanal electrocochleography or promontorial testing, temporal bone CT and MRI were performed. After the test periods of randomised 2 × 3 weeks (3-week BAHS-testing on head band and 3-week CROS-testing) the participants were divided into three groups: Group A: participants who decided on a BAHS, group B: participants who decided on a CROS hearing aid, and group C: participants who decided on a CI. The participants of groups A and C were then implanted . The outcomes of some patients were discussed in previous publications , 5.All study participants completed a 3-week test phase with CROS and BAHS. Which device was tested first was determined randomly. After each of the test phases, the participants filled out questionnaires in which their subjective experiences were recorded. Hearing tests were also performed to determine the objective hearing ability. In addition, all participants who were in principle eligible for a CI were informed about the possibility of CI treatment. After the test phase, the participants could decide whether they wanted to continue participating in the study and what kind of hearing rehabilitation they wanted. Therefore, the number of participants in each group is different. The tests were repeated after 12 months for the participants in groups A and B. For group C participants, the tests were repeated after 6 and after 12 months. Testing after 6 months was performed routinely as part of rehabilitation  sentence test . Speech Localisation: Localisation abilities were tested in a sound-isolated room with seven loudspeakers positioned in a frontal semicircle 2 m in diameter with a distance of 30° in the horizontal plane around the participant at head level. Sentences of the Oldenburg sentence test (OLSA)  were useHearing Handicap Inventory for Adults (HHIA): This ten-item questionnaire records the subjectively perceived limitation on a social and emotional level that the patient brings into the study due to his single-sided deafness . Since tSpeech, Spatial and Qualities of Hearing Scale (SSQ): This 3-section questionnaire assesses speech understanding, spatial hearing, and hearing quality with a scoring system of 0 to 10 for each item. Unable to hear is represented by 0 and 10 means hears perfectly .Statistical analysis was carried out in GNU R  and illustrated by Box–Whisker plots. The Shapiro–Wilk test was used to check the data for normal distribution. The Kruskal–Wallis test was performed for comparison of the three groups (A–C) in SSQ, localisation ability and speech recognition in noise. For post hoc analyses, pairwise comparison with the Wilcoxon-rank tests using Bonferroni correction was applied. A level of significance of 0.05 was applied in all analyses.p = 0.359). However, we found a difference between the groups in the duration of deafness (p = 0.007). The duration of deafness was shorter for group C than in the other groups . After the two trials, 16 participants chose BAHS , 13 participants chose CROS , and 30 participants chose CI . 20 participants decided against treatment and 10 participants stopped the study. The main reason for SSD was sudden hearing loss (n = 29), followed by unclear reason of SSD since childhood (n = 13). For further aetiologies, see Table In this study, 89 adult participants were included with an average age of 55.8 years and an average period of single-sided deafness of 10.7 years  felt no hearing handicap (0–8 points), 40.0% (22 of 55) felt a mild-to-moderate hearing handicap (10–24 points) and 54.5% (30 of 55) a significant hearing handicap (26–40 points). Four patients did not return the questionnaire. Group A rated their hearing handicap on average with 26.8 points (SD 9.6), Group B with 18 points (SD 8.9) and Group C with 28.2 points (SD 9.9). BAHS (9 of 15) and CI (19 of 29) were mostly chosen by participants with severe impairment and CROS (8 of 11) by participants with mild-to-moderate impairment.Results of HSM sentence test at different time points, different treatment options, and different presentation configurations are shown in Fig. p = 0.4351, SssdNnh: p = 0.06921, SnhNssd: p = 1; Fig. p = 0.003; median unaided = 0%; median CROS = 27.83%; Fig. p = 0.008; median unaided = 0%, median BAHS 12 m = 40.59%; Fig. Group A: After the 3-week test period with a headband, no significant improvements for BAHS were found in all test configurations .Group B: After the 3-week test period with the CROS system, no significant improvements were found in all test configurations (S0N0: p = 0.088) configuration compared to the untreated situation. In the SssdNnh configuration, all 3 devices significantly improved speech understanding . In the SnhNssd configuration, the CROS resulted in a significant decrease in speech understanding compared to the unaided situation (unaided vs. CROS: p = 0.001).Group C: BAHS testing, CROS testing and CI after 12 months showed no differences in the S0N0 (p = 0.017) and better speech perception in the SnhNssd configuration compared to BAHS group (p = 0.002) and CROS group (p < 0.001).Comparing the 12-month results between the three groups showed significantly better speech perception with CI in the S0N0 configuration compared to the CROS group (p < 0.001) compared to the unaided conditions. No differences were found in Groups A and B. Comparing the 12-month results there was a significant difference between Group B and C .Localisation errors of all three groups are shown in Fig. p = 0.024) and after 12 months . No difference was found between the unaided situation (median 5.07) and group B after the CROS test phase  and after 12 months . A significant difference was found between the unaided situation (median 3.05) and group C after 6 months  and after 12 months . In all groups no differences were found between the test phase and after 12 months. No differences were found between the three groups after 12 months  and group A test phase  and, although not significant, between the unaided situation and after 12 months . Also in group B, differences were found between the unaided situation (median 2.21) and after the test phase  but not between the unaided situation and after 12 months . In group C, differences were found compared to the unaided situation (median 2.26) after 6  and after 12 months . In all groups no differences were found between the early test phase and after 12 months. No differences were found between the three groups  and after the test phase  and group C (3.36) after 12 months . In contrast to our 2011 study , we inclNumerous studies have shown improved speech perception and sound localization with a CI in SSD compared to untreated situations , 16 or tSound localisation was best with CI, with a reduction of the localisation error of 10.93° compared to the unaided situation. The improvement to localise sound by a CI has been shown in numerous studies (for reviews see: –23). We Based on the SSQ questionnaire, speech understanding is improved by BAHS and CI, but not by CROS. Spatial hearing improves subjectively after 12 months only with CI. Hearing quality did not improve statistically with the three devices. Hearing-related quality of life can be measured by the SSQ scale and by the abbreviated profile of hearing aid benefit (APHAB). The latter measures ease of communication, background noise, reverberation and aversion to loud sounds. A meta-analysis found significant benefits for BAHS for all subscales of the APHAB except aversion to loud sounds, for CROS significant benefits were only found for background noise and reverberation. A meta-analysis for SSQ did not identify significant effects of BAHS or CROS compared to the unaided situation, but significant decreases in listening difficulty with CI was found on all subscales . In our A disadvantage of the study is the greater ceiling effect when using the HSM with fixed noise and speech level instead of an adaptive procedure. However, since the same test was performed in all three groups, the groups are comparable. A further disadvantage is the different size of the groups, which cannot be avoided, because the patient is allowed to choose the device and is not randomly assigned to a group. Therefore, the groups are not randomized, which results in a further inevitable bias.In summary, the best results regarding therapy of SSD are possible with a CI, followed by BAHS. This was evident both in objective tests and in the subjective questionnaires. Nevertheless, an individual decision is required in each case as to which therapy option for SSD is best for the patient. Above all, the patient's subjective impairment and expectations should be included in the decision-making process.


Objective: To identify and report novel variants in the TMPRSS3 gene and their clinical manifestations related to hearing loss as well as intervention outcomes. This information will be helpful for genetic counseling and treatment planning for these patients.Methods: Literature review of previously reported TMPRSS3 variants was conducted. Reported variants and associated clinical information was compiled. Additionally, cohort data from 18 patients, and their families, with a positive result for TMPRSS3-associated hearing loss were analyzed. Genetic testing included sequencing and copy number variation (CNV) analysis of TMPRSS3 and the Laboratory for Molecular Medicine’s OtoGenome-v1, -v2, or -v3 panels. Clinical data regarding patient hearing rehabilitation was interpreted along with their genetic testing results and in the context of previously reported cochlear implant outcomes in individuals with TMPRSS3 variants.Results: There have been 87 previously reported TMPRSS3 variants associated with non-syndromic hearing loss in more than 20 ancestral groups worldwide. Here we report occurrences of known variants as well as one novel variant: deletion of Exons 1–5 and 13 identified from our cohort of 18 patients. The hearing impairment in many of these families was consistent with that of previously reported patients with TMPRSS3 variants . Four patients from our cohort underwent cochlear implantation.Conclusion: Bi-allelic variants of TMPRSS3 are associated with down-sloping hearing loss regardless of ancestry. The outcome following cochlear implantation in patients with variants of TMPRSS3 is excellent. Therefore, cochlear implantation is strongly recommended for hearing rehabilitation in these patients. It accounts for about 70–80% of congenital hereditary hearing loss. ARNSHL is an extremely heterogenous condition as more than 98 loci have been mapped and 77 causative genes have been identified to date , the stria vascularis, and cochlear aqueducts of fetal cochlea . They assert that having two “severe” pathogenic variants leads to profound deafness with prelingual onset (DFNB10), whereas a single ‘severe’ pathogenic variant in trans with a milder TMPRSS3 pathogenic variant yields an initially less severe, but progressive and post-lingual onset hearing loss (DFNB8) (TMPRSS3 gene encodes for a transmembrane serine protease which is expressed in SGNs (Patients with pathogenic variants in the  (DFNB8) . The TMP in SGNs . TherefoTMPRSS3 variants and present a novel variant along with their associated hearing phenotypes. We also aggregate reported outcomes and present new findings regarding the therapeutic effects of cochlear implantation (CI) in patients with pathogenic TMPRSS3 variants. Together, this information may assist with genetic counseling and treatment planning for patients with TMPRSS3 variants.In this study, we compile previously reported https://hereditaryhearingloss.org; https://www.ncbi.nlm.nih.gov/clinvar/). The titles and abstracts were screened using following inclusion criteria: 1) written in English, 2) dealing with non-syndromic hearing loss, and 3) reporting human data.Literature databases were searched using different combinations of keywords such as “transmembrane serine protease 3,” “TMPRSS3,” “ear,” “hearing loss,” “non-syndromic hearing loss,” and “cochlear implantation.” The databases searched were PubMed, Google Scholar, and two selected gene database websites , who were largely White, though Family A was a consanguineous White Egyptian family, Family B was “mixed,” and Families M and I were of Hispanic or Latino ethnicity. Of the patients with characterized hearing loss, the severity ranged from moderate to profound with some individuals experiencing congenital onset and others experiencing a childhood onset or an onset in the second decade of life. Patients were referred to the Laboratory for Molecular Medicine (LMM) at Mass General Brigham Personalized Medicine  from 2009 to 2017. Patients were referred from various clinics and hospitals across the United States. The LMM collected information pertinent to the nature of the hearing loss in the patients (if available) including family history of hearing loss and/or disease, audiological testing, temporal bone CT/MRI results, and CI status. Further information was requested through physicians via the Mass General Brigham Human Research Committee’s IRB protocol for the study of the genetics of hearing loss. Patients were selected based on whether they received a positive result for TMPRSS3, or LMM’s OtoGenome-v1,-v2, or -v3 panels.Patient DNA was extracted from whole blood from patients who were referred to the LMM for hearing-loss genetic testing. Our cohort contains patients from 2009 to 2017. The genetic testing varied for each patient based on the judgment of the ordering physician and the nature of the patient’s hearing loss. Testing was performed by single gene sequencing that included ACTG1, ATP6V1B1, BSND, CCDC50, CDH23, CLDN14, CLRN1, COCH, COL11A2, CRYM, DFNA5, DFNB31, DFNB59, DIAPH1, ESPN, ESRRB, EYA1, EYA4, GIPC3, GJB2, GJB3, GJB6, GPR98, GPSM2, GRHL2, GRXCR1, HGF, ILDR1, KCNE1, KCNQ1, KCNQ4, LHFPL5, LOXHD1, LRTOMT, MARVELD2, MIR183, MIR96, MSRB3, MTRNR1 (12S rRNA), MTTS1 (tRNAser(UCN)), MYH14, MYH9, MYO15A, MYO1A, MYO3A, MYO6, MYO7A, OTOA, OTOF, PCDH15, PDZD7, POU3F4, POU4F3, PRPS1, RDX, SERPINB6, SLC17A8, SLC26A4 (PDS), SLC26A5, TECTA, TIMM8A, TJP2, TMC1, TMIE, TMPRSS3, TPRN, TRIOBP, USH1C, USH1G, USH2A, and WFS1.The LMM’s bioinformatics pipeline for targeted next generation sequencing (NGS) panels has been described previously . PatientPDZD7 and SLC26A5 genes were removed and the STRC gene was added. In addition, copy number variant (CNV) detection was added using VisCap as previously described , or droplet digital PCR for CNVs called by VisCap , likely pathogenic (LP), of uncertain significance (VUS), likely benign, or benign. The VUS category was further subdivided into VUS-5, -4, and -3 where VUS-5 indicated leaning towards pathogenic, and VUS-3 indicated leaning towards benign. Likely benign and benign variants are not reported in this article but were submitted to ClinVar (www.ncbi.nlm.nih.gov/clinvar/) along with all other variants observed at the LMM.The LMM’s early variant classification methods are as previously described  and wereTMPRSS3 variants and present one novel variant identified from our cohort , specifically the combination of PVS1 (predicted loss of function), PM2 (absence in gnomAD), and PM3 . The most commonly identified variants were p.Thr70fs*19 and p.Ala138Glu. Eight patients had congenital hearing loss, four of whom had biallelic pLOF variants.Our cohort included 18 patients—7 females and 11 males—with ages ranging from 3 months to 36 years . 15 pati5 and 13 . This noidelines  with spe. It is unclear when the patient underwent CI. However, at a follow up at 4 years of age, the patient had functional speech. Clinical records indicated that the patient had ongoing articulation errors and required speech therapy but was able to maintain adequate hearing. The second patient, from family K, was compound heterozygous for p.Glu104Lys and p.Ala306Thr. Clinical records have suggested positive CI outcome for her moderate-profound hearing loss. The remaining two patients who underwent CI were the siblings from family A who both had profound congenital hearing loss and were homozygous for a deletion of Exons 1–5 and 13. Their current hearing status is unknown.Four patients in our cohort underwent CI, and outcome information was available for two patients. The first patient, from family B, was found to have congenital profound hearing loss and was homozygous for p.Thr70fs*19TMPRSS3 variants have not been well characterized. It has been previously shown that the frequency of TMPRSS3-induced ARSNHL was low in White individuals (TMPRSS3 gene variants (TMPRSS3 variants and associated phenotypes to best counsel patients.The genotype-phenotype correlations of ividuals . Howevervariants . As adopIn our cohort of 18 patients, 15 of whom were White, the most frequently observed variants were p.Thr70fs*19 and p.Ala138Glu implying that those were either hot spots or founder variants. The combination of the p.Thr70fs*19 frameshift variant with a missense variant appeared to cause sloping hearing loss that varied in severity. Biallelic pLOF variants appeared to cause congenital profound hearing loss. This phenotype information is valuable when trying to understand potential patient prognosis based on genetic testing results.TMPRSS3 variants have reported variable results. In one study, poor outcomes following CI in patients with TMPRSS3 variants were attributed to the expression of the TMPRSS3 gene in SGNs as opposed to other locations in the cochlea such as the membranous labyrinth (TMPRSS3 variants may have continued loss of SGNs over time which could contribute to ongoing hearing deterioration even after CI. However, recent studies have shown predominantly positive outcomes following CI in patients with TMPRSS3 variants (TMPRSS3 variants reported positive outcomes with no evidence of SGN degeneration leading to decreased performance over time (labeled indications for CI. However, off-label implantation has been shown to be beneficial and is being employed much more frequently at major academic medical centers (Previous studies on the role of CI in patients with abyrinth . These avariants . This diver time . Furtherver time . Even so centers .TMPRSS3 variants. Active intervention with CI is likely to be beneficial, particularly in patients in whom residual hearing is preserved. It is imperative that the benefits of CI are made clear when counseling patients on their potential treatment options.Taken together with the positive clinical outcomes following CI in two patients from our cohort, it is evident that CI is a promising treatment strategy for patients with


Hearing loss is the third leading cause of years lived with disability. It is estimated that 430 million people worldwide are affected, and the number of cases is expected to increase in the future. There is therefore increased pressure on hearing health systems around the world to improve efficiency and reduce costs to ensure increased access to quality hearing health care. Here, we describe the User-Operated Audiometry project, the goal of which is to introduce an automated system for user-operated audiometric testing into everyday clinic practice as a means to relieve part of this pressure. The alternative to the existing referral route is presented in which examination is executed via the user-operated system. This route is conceptualized as an interaction between the patient, the system, and the hearing care professional (HCP). Technological requirements of the system and challenges that are related to the interaction between patients, the user-operated system, and the HCPs within the specific medical setting are discussed. Lastly, a strategy for the development and implementation of user-operated audiometry is presented, which includes initial investigations, a validation study, and implementation in a real-life clinical situation. Hearing loss is the third leading cause of years lived with disability . The WorTreatment of hearing loss often involves the examination of hearing function, the selection and fitting of hearing aids, and the evaluation of hearing-aid performance. As part of the initial assessment, the pure-tone audiometry is time-consuming, as testing time may exceed 20 min , 8 and sHere, we describe the User-Operated Audiometry (UAud) project, the goal of which is to introduce an automated system for user-operated audiometric testing into everyday clinical practice. Importantly, the user-operated system is not intended to replace the audiological assessment done by an HCP, but rather to offer an alternative to manual audiometric testing when applicable. Furthermore, the UAud project focuses on the user-operated diagnostic examination, in the clinical environment and with calibrated clinical devices. Although these approaches, such as asynchronous tele-audiology , have shThe purpose of this perspective article is (a) to briefly review previous relevant related work about user-operated audiometry, (b) to describe the scope and focus of the UAud project, (c) to create a perspective on the challenges and possible barriers related to the inclusion of the new examination paradigm, and (d) to present a strategy for addressing these challenges and effectively implement user-operated audiometry in the daily practice.The opportunities of automated audiometry have been explored since the beginning of the computer age  and has Considerable research contributions have been focused on the Automated Method for Testing Auditory Sensitivity (AMTAS®) test, a single-interval, forced choice method (yes-no paradigm) task with an adaptive algorithm for pure-tone detection thresholds . This teThe automatization of presenting pure tones to a patient while concurrently analyzing the patient's responses does not present many technical challenges and has the potential to be included in a user-operated version suitable for a broad part of the population. However, the implementation of other user-operated audiological tests such as speech audiometry is more challenging. Research efforts have been made in the direction of automatizing speech-in-noise recognition , 30, andThe assessment of the patient's ability to extract the essential features of the speech signal may lend itself to a more practical solution. The Audible Contrast Threshold (ACT™) is a new clinical test measuring spectro-temporal modulation sensitivity, in which the subject's task is to discriminate between spectro-temporally modulated noise and non-modulated noise. The idea that the similarity of the spectro-temporal characteristics of the modulated stimuli and real speech would make sensitivity to spectro-temporal modulations a good predictor of speech-in-noise performance has been investigated by several research groups –37 with The existing clinical procedure for hearing-aid fitting consists of three main steps. Step 1: examination of hearing–audiometry, step 2: initial fitting of the hearing aids, and step 3: evaluation of hearing aid performance and re-adjustment if needed see . NormallThe UAud project explores an alternative procedure by freeing the HCP from the major part of the first step  and instead introducing the user-operated system, while all the tasks and responsibilities of the HCP in steps 2 and 3 remain unchanged. This new procedure can be conceptualized as a human-digital system-human interaction . The three parties interact more than once and in more than one way see , but theIn order to better understand the dynamics of the 3-parties system , it seems useful to have a detailed perspective of the relevant characteristics of the parts, . Humans are goal-oriented and goal-directed . They leDigital technology comes with its own pros and cons. Compared to humans, it is typically governed by clearer and known rules, so it can be standardized comparatively easily, and still offers some versatility through settings in the system. On the other hand, digital technology tends to become less adaptable after its release, and paradigm changes may require completely new technology to be developed, whereas a human might only need short retraining. Thus, every detail on every process and all potential pitfalls/bugs, must be thought of and addressed in advance before implementation. Excluding an arguably significant, still not relevant to the present study, part of current technology, i.e., artificial intelligence, one could argue that humans learn while technology is set.Bringing together humans and digital technology is a challenge on its own, as large differences between them may negatively affect their interaction. Making digital technology more user-friendly and measuring the quality of the interaction is a wide field of study of its own and has a fast-growing body of research output in the last few decades. Indicatively, a search in Scopus with keywords [“usability” AND “technology”] yields 717 review studies alone (searched on 8-March-2021), while there is an increasing interest on usability for health evaluation and intervention tools [for reviews see –47]. In Insights on the effects of the introduction of user-operated audiometry can be gained by comparing with audiometry operated by an HCP. Focus should be given on those aspects of human and digital technology that are crucial for the quality of the hearing examination results. In The UAud project aims to explore the possibilities of implementing user-operated audiometry in everyday clinical practice. The technological progress on automated audiometry of the past decades will be further developed, evaluated, and implemented in the clinic in the form of a system for user-operated testing of air-conduction pure-tone audiogram and ACT™. As the motivation behind the project is to free work hours from HCPs dedicated to the hearing examination, the system must be handled by the patient ideally without any supervision. All actions taken by the HCP , 23 suchThe requirements for successful implementation of the user-operated audiometry system are:- The establishment of the necessary software, hardware, and testing environment.- Acceptable usability and user experience of the system's software and hardware.- Strategies to deal with situations such as patients needing further instructions or other considerations (patient's presenting tinnitus).- The system must be designed to ensure that the patient's attention is adequately focused on the task during the examination.- Optimal time efficiency, that is, the test must be accurate and reliable while avoiding causing patient fatigue due to extensive test time.- Effective supervision, that is, the system must assess the quality of the examination, and give recommendation for further testing if necessary.Further, the UAud project must account for the specific setting in which the system will be implemented. The setting includes (a) the medical context, that is, hearing health care and specifically the audiological examination  before the examination , (b) during the examination , and (c) after the examination . These factors may affect the examination itself, and further influence the HCP's confidence in the validity of the examination and consequently his/her decisions in the rehabilitation process.- The lack of the positive effect on the patient due to presence of a human medical expert during the examination. This may partially affect the trust, knowledge, regard, and loyalty that characterizes the patient-HCP relationship .- Intrinsic factors of the patient: computer skills, biases against technology, cognitive decline, and comorbidities.- HCPs, as all clinicians, are very cautious and demand high quality and evidence before accepting a new examination paradigm as part of their everyday clinical practice . It is r- HCPs work as a community, at least to a degree . Experie- The potential disruption to standard operating procedures, e.g., changing appointment times, effects on allocation of human and physical resources.The success of the UAud project relies on the extent to which the user-operated audiometry system meets the aforementioned requirements and is accepted by both patients and HCPs, enabling wide adoption in audiological practice. Here, a research plan is presented which includes (1) initial investigations, (2) a validation study where this system will be evaluated in a randomized clinical trial, and (3) implementation in a semi-large scale within real-life clinical conditions.The initial investigations consist of (a) prototyping and user-interaction design of the user-operated solutions, (b) evaluation of the equipment and testing environment toward a usable system, (c) implementation and validation of a user-operated ACT™ test, and (d) identifying barriers on implementation. At this early stage, a detailed record of patients' and HCPs' concerns that will inform the whole project's research plan is needed. This will include semi-structured interviews  and ques- How can the design of the user interface maximize the internal/external motivation and minimize distractions?- How do the patients interact with the system when doing a new audiometric test?- Which is the preferred paradigm for assessing the ACT™ in a user-operated test?- What is the effect of the user (instead of expert) placing of headphones on audiometry and ACT™? How to ensure its quality?- What is the most effective design for the set of instructions required for handling both software and hardware? How can the system be designed in terms of both content and mode  to guarantee that a majority of patients can successfully complete the test?Hearing rehabilitation entails different types of interventions. Part of these interventions include the hearing-aid selection, provision, and fitting, which make use of the individual audiometric thresholds. The purpose of the validation study is to demonstrate that the quality of the intervention is not influenced by the modality of the hearing test . A randomized double blind clinical trial will be conducted on two groups of adult patients with a treatable hearing loss (125 in each group). HCPs will provide the intervention based on audiometric thresholds without knowledge of the modality used to obtain them. Two months after the hearing aid fitting, patients will be examined with a test battery which will include self-report outcome measures and an examination of speech intelligibility.The UAud system will be implemented in a real-life situation, involving the allocation of resources for a new workflow in the selected clinics. The implementation of user-operated audiometry will be carried out at Odense University Hospital in Odense and Svendborg, as well as at two private ENT clinics. It will include a total of at least 250 patients. This is probably the most challenging part of the project, as there will be a need for clinicians adopt the user-operated audiometry as part of their daily work. Therefore, an effective change in the hearing healthcare service should involve different phases (All authors have made contributions to the manuscript, participated in the conceptualization, reviewed, and agreed with the final version of the manuscript.This work was supported by Innovation Fund Denmark Grand Solutions 9090-00089B and the William Demant Foundation.RS-L is employed by Interacoustics A/S. 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.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.


Lawsonia intracellularis, an intracellular bacterial pathogen that primarily colonizes the ileum. In this study, we evaluated changes to the microbiome of the ileal mucosa, ileal digesta, cecal digesta, and feces subsequent to challenge with L. intracellularis and to an oral live vaccine against L. intracellularis. Given that gut homogenates have been used since 1931 to study this disease, we also characterized the microbial composition of a gut homogenate from swine infected with L. intracellularis that was used as challenge material. The L. intracellularis challenge led to a dysbiosis of the microbiome of both the small and large intestine marked by an increase of pathobionts including Collinsella, Campylobacter, Chlamydia, and Fusobacterium. This microbiome response could play a role in favoring L. intracellularis colonization and disease as well as potentially predisposing to other diseases. Vaccination altered both small and large intestine microbiome community structure and led to a significant 3.03 log10 reduction in the amount of L. intracellularis shed by the challenged pigs. Vaccination also led to a significant decrease in the abundance of Collinsella, Fusobacterium, and Campylobacter among other microbial changes compared with non-vaccinated and challenged animals. These results indicate that L. intracellularis infection is associated with broad changes to microbiome composition in both the large and small intestine, many of which can be mitigated by vaccination.Porcine proliferative enteropathy remains one of the most prevalent diseases in swine herds worldwide. This disease is caused by  Lawsonia intracellularis is a Gram-negative intracellular bacterial pathogen and the causative agent of porcine proliferative enteropathy (PPE). Infection with L. intracellularis has been estimated to occur in more than 90% of swine farms worldwide , Law , and LawVac . The LawVac group was vaccinated with the oral live vaccine  after 5 days of acclimation. To investigate the impact of the vaccine alone on the microbiome, a group of six random pigs in the Control and LawVac groups were necropsied at 21 days post-vaccination [0 days post-infection (dpi)]. At 6 weeks of age, 3 weeks post-vaccination, the Law and LawVac groups were challenged with a gut homogenate containing 4 × 107L. intracellularis organisms. To evaluate the microbiome response at different stages of infection, six pigs were randomly selected from each treatment group  and euthanized at 7, 21, and 28 dpi. To minimize the exposure of the Control group to L. intracellularis, this treatment group was housed in a separate barn from the challenged and vaccinated groups. Separation of animals within the same room has been found to be insufficient to prevent transmission of L. intracellularis .The animal protocol used was approved by the Boehringer Ingelheim Animal Health USA Inc., Institutional Animal Care and Use Committee (protocol number 100896); and all experiments were performed in accordance with relevant guidelines and regulations. All pigs used in this study were obtained from a sow herd with no previous history of clinical signs from L. intracellularis preferentially infects epithelial cells located in the terminal ileum, we also collected mucosal scrapings from this segment as previously described, with the addition of RNAlater   . In addiL. intracellularis-specific antigens in the tissues as previously described , as well as on 0, 7, 21, and 28 dpi. Samples were tested by the immune peroxidase monolayer test at the University of Minnesota Veterinary Diagnostic Laboratory . The entescribed . IHC wasDNA was extracted from 250 mg of each sample using the QIAGEN DNeasy PowerSoil HTP 96 Kit  following the manufacturer's protocol. The resulting DNA was stored at −80°C. The V4 region of the 16S rRNA gene was amplified from DNA samples and sequenced on the Illumina, Inc.  MiSeq platform  at the University of Minnesota Genomics Center , as previously described .Raw reads were processed using the DADA2 pipeline (v2.0)  in R v3. Forwardp-values were adjusted for multiple testing using the Benjamini–Hochberg procedure.For alpha diversity analyses, cecal digesta, feces, ileal mucosa, and ileal digesta samples were rarefied to 12,027, 8,156, 2,447, and 12,223 reads, respectively. ASV richness and the Shannon diversity index were calculated with the R package, phyloseq (v1.28.0) . To assephyloseq_transform_css function. The Bray–Curtis dissimilarities and weighted UniFrac distances were then calculated using the phyloseq distance function. Differences in microbial composition between the treatment groups and dpi were visualized with principal coordinate analysis (PCoA) plots with multivariate t-distribution ellipses. Significant differences in composition between groups were assessed by permutational multivariate analysis of variance (PERMANOVA) tests with 999 permutations with the adonis function from the R package, vegan (v2.5.5)  was conducted with zero-inflated Gaussian mixture models using the fitZIG function from the R package, metagenomSeq (v1.26.3)  was used to normalize the unrarefied data using the phyloseq (v2.5.5) . The betv1.26.3)  with defL. intracellularis infection and gross PPE lesions were homogenized and diluted in sucrose potassium glutamate diluent and Dulbecco's Modified Eagle Medium (DMEM) prior to intragastric inoculation of animals.The preparation of gut homogenate challenge material followed procedures previously described . BrieflyL. intracellularis present in fecal samples, cecal digesta, and gut homogenate was performed by qPCR  480 LightCycler per manufacturer's protocol. A standard curve was included in each run for the quantification of L. intracellularis. Statistical differences in fecal shedding of L. intracellularis were assessed by Wilcoxon's rank-sum test.Quantification of  by qPCR . BrieflyWith the objective of gaining a broad understanding of the bacterial and viral taxa of the gut homogenate inoculum material, shotgun metagenomic analysis was performed. Metagenomic characterization of the gut homogenate challenge material was performed at Newport Laboratories . DNA and RNA extraction was performed using MagMax Core Nucleic Acid Purification Kit (Thermo Fisher). cDNA was synthesized from RNA with the Maxima H Minus Double-Stranded cDNA Synthesis Kit (Thermo Fisher). Library preparation was performed with the Nextera XT kit (Illumina), and sequencing was performed on MiSeq sequencer with 2 × 300 bp V3 chemistry (Illumina). Sequence read files were uploaded on to Illumina BaseSpace for analysis. Scaffolds were created using Illumina BaseSpace application SPAdes Genome Assembler. Metagenomic analysis was performed using Illumina BaseSpace application Kraken (v1.0.0) . The genL. intracellularis, which represented approximately 0.40% of total reads and 34.9% of bacterial reads  group, shedding increased from 4.3 log10 organisms per gram at 7 dpi to 7.87 log10 organisms per gram at 21 dpi and then decreased to 6.69 log10 organisms per gram at 28 dpi  as compared with non-vaccinated Law pigs  pigs with positive IHC staining, while the Law group had a median lesion score of 2 with five of six pigs (83%) with positive IHC staining. While both Law and LawVac groups had macroscopic lesions at 21 dpi, only the Law group had macroscopic lesions characteristic of L. intracellularis infection at 28 dpi with two of six (33%) pigs having a lesion score of 2 and 4, respectively. No macroscopic lesions were found in the LawVac group at this time point. No macroscopic lesions were found at 0 or 7 dpi. At 3 weeks post-vaccination, only one of the 24 (4.2%) LawVac animals had serum antibodies against L. intracellularis. This proportion increased to 23.5% (4/17), 90.9% (10/11), and 83.3% (5/6) at 7, 21, and 28 dpi, respectively. All Law animals were seronegative at 0 dpi, and seroconversion increased to 33.3% (6/18), 63.6% (7/11), and 100% (6/6) of pigs with serum antibodies against L. intracellularis at 7, 21, and 28 dpi, respectively. Control animals remained negative for all diagnostic measures of L. intracellularis infection throughout the trial.To better understand how the composition of the gut microbiome changed during infection with t 28 dpi . Pigs inLaw pigs . Both LaL. intracellularis, a beta diversity analysis was performed among the challenged and non-challenged Law and Control groups utilizing the Bray–Curtis dissimilarity index. A clear effect of challenge on community structure was observed. L. intracellularis infection, the terminal ileal mucosa, no significant differences were observed at 7 dpi  and 28 dpi , but similar to ileal mucosa, differences also increased as infection progressed at 21 dpi  and 28 dpi ; this difference was not present at −23 dpi . Treatment group explained a drastically increased proportion of microbial community variation as infection progressed, with PERMANOVA R2-values of 0.095, 0.31, and 0.30 at 7, 21, and 28 dpi, respectively . Finally, a similar trend to other communities was observed in the cecal digesta, with no significant differences observed at 7 dpi  and an increase in the distinction between treatment group microbial communities as infection progressed at 21 dpi  and 28 dpi . Interestingly, at both 21 and 28 dpi, Slackia was more abundant in Law than Control pigs  at this time point. At 21 dpi, many more differentially abundant bacteria were found; among those most abundant in Law pigs were Lawsonia, Chlamydia, Collinsella, and Fusobacterium , Lawsonia was already significantly differentially abundant among groups in feces , a significant difference in community structure was found between LawVac and Law pigs in feces . Vaccination had a significant effect (p < 0.05) on the community structure of ileal mucosa, ileal digesta, and cecal digesta relative to non-vaccinated Control pigs at 0 dpi (data not shown). Investigating composition further, at 0 dpi, there were 73 significantly differentially abundant genera between LawVac and Law pigs in feces  to 28 dpi  and 28 dpi  time points between the LawVac and Law groups ; and at 28 dpi, each group had a distinct community structure , it was clear that infection and proliferation of L. intracellularis occurred, as Lawsonia-infected animals shed on average 7.87 log10 organisms/gram at 21 dpi. Along with detection by quantitative real-time PCR, 16S rRNA gene analysis also confirmed the presence of Lawsonia, which was significantly differentially abundant between Control non-infected and Law infected groups in feces, ileal mucosa, ileal digesta, and cecal digesta. Typical macroscopic lesions and positive IHC staining for the presence of L. intracellularis in terminal ileum tissue were also observed in these animals.When analyzing the challenge dose of L. intracellularis infection and gut microbiome composition. This study is not the first description of bacteria other than Lawsonia being enriched in the intestine of pigs challenged with a gut homogenate. McOrist et al.  decrease in abundance of Collinsella in cecal digesta and of Prevotella 2 in ileal mucosa (data not shown). Again, similar to previous findings, several of the sequences of Collinsella were closely related those of Collinsella aerofaciens and sequences of Prevotella to Prevotella copri. These have been considered pathobiont bacteria, as they have the capacity to induce inflammatory responses, which could favor Salmonella infection  also altered the abundance of other bacterial members of the gut microbiome. Perhaps this indicates that L. intracellularis is the primary causative agent of PPE and driver of dysbiosis, which when controlled with an effective mucosal immune response allows for minimizing its effects on microbial community composition. It is also possible but unclear if the changes observed in the gut microbiome by the oral vaccine alone or prior to challenge had any effect in the protection conferred to L. intracellularis.It is remarkable that a vaccine that only contains antigens to one bacterium  loss of beneficial microbial organisms, (ii) expansion of pathobionts, and (iii) loss of overall microbial diversity . PathobiL. intracellularis with other bacteria present in the swine gut that could contribute to the development and severity of disease, many of which were found to be altered by vaccination in this study. Future studies should focus on investigating microbiome changes induced by L. intracellularis in natural field conditions as well as utilizing gnotobiotic models with different defined microbial communities to allow for more conclusions on the exact contribution of organisms other than L. intracellularis in the establishment and severity of PPE.Our findings support the strong association of https://www.ncbi.nlm.nih.gov/bioproject/728719.The sequencing datasets generated for this study can be found in the NCBI BioProject repository under ID PRJNA728719, The animal study was reviewed and approved by the Boehringer Ingelheim Animal Health USA Inc., Institutional Animal Care and Use Committee and all experiments were performed in accordance with relevant guidelines and regulations.FL and RI conceived the study. BW, EM, BPW, and TJ conducted microbiome analysis. FS conducted metagenomic analysis of gut homogenate. EV, DB, and FV conducted pathological measurements and collected samples. FL, RI, and TJ wrote the manuscript. All authors have read and critically reviewed the manuscript.This study was partially funded by Boehringer Ingelheim Animal Health USA Inc., Duluth, GA. FL and FS are employees of Boehringer Ingelheim Animal Health USA Inc. DB is employed by Gut Bugs Inc. 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.


Acromegaly is a complex endocrinological disorder commonly caused by hypersecretion of growth hormone (GH) typically due to pituitary gland tumors. Patients with acromegaly who are successfully treated and biochemically managed have a reasonably average life expectancy. However, it causes a cascade of multi-systemic involvement throughout the patient’s life, including cardiovascular, neuropsychiatric, respiratory, metabolic, neurological, neoplastic, and gastrointestinal involvement, resulting in a higher rate of hospitalization, lower quality of life, and a shorter life expectancy. Although cardiovascular complications are the primary cause of death in patients with acromegaly, malignancy is now emerging as a major killer in these individuals. Colorectal carcinoma has been reported to be prevalent in acromegaly individuals. This review article has compiled studies to demonstrate a link between acromegaly and colorectal neoplasia, intending to provide a strong foundation for their clinical relationship. This article has summarised a potential pathogenic mechanism and provided insights into the clinical presentation of such patients. Furthermore, this article has provided a brief overview of current screening recommendations for colorectal neoplasia in acromegaly patients.  Acromegaly is an endocrinological disorder characterized by an abnormally elevated growth hormone (GH) level in the serum predominantly caused by a pituitary adenoma ,2. PierrAlthough the clinical presentation of acromegaly is relatively apparent with regards to the physical appearance of the patients, the workup usually begins with an elevated IGF-1 level as it is an indicator of GH function. It is confirmed with an unsuppressed GH concentration after an oral glucose tolerance test (OGTT) . RadioloAcromegaly and colorectal polypsAcromegaly is most commonly caused by an anterior pituitary somatotrophic tumor that secretes GH, also known as somatotropin . GH is aSince IGF-1 receptors are expressed in both normal and malignant colorectal epithelia, when activated by IGF-1, the receptor-ligand complex suppresses apoptosis and enables progression through the cell cycle by activating signal transduction pathways critical for cell growth and survival  were found to have polyps (p=0.001). Acromegalic patients exhibited a higher number and larger size of polyps. The most prevalent location was the rectosigmoid area, indicating that individuals with acromegaly are at an increased risk of developing colorectal polyps than the general population , and endoscopic mucosal resection (EMR) if detected at an early stage. Endoscopic management modalities are used to treat polyps based on their size and histological features . Polyps Acromegaly and colorectal carcinomaThe IGF-1 axis plays a vital role in carcinogenesis by promoting cellular turnover, leading to the accumulation of molecular alterations that influence colon carcinoma development . Colon cBattistone et al. recently published a case-control study that comprised 70 acromegaly patients and 128 healthy controls. Advanced neoplastic lesions were found in 22 (31.4%) of patients and nine (7.0%) of controls : 6.06); advanced adenomas were found in 18 (27.3%) and nine (7.0%) of patients and controls, respectively , and colorectal carcinomas were discovered in four (5.7%) and zero (0.0%) of patients and controls, respectively (p=0.0063), indicating that acromegaly patients had a higher risk of developing colon cancer . In 10 individuals, colon cancer was discovered. In comparison to the general population, the SIRs for colon cancer in acromegaly patients was 17.4 (95% CI: 4.74-44.55) for females and 19.0 (95% CI: 5.18-48.64) for males, indicating a substantial risk of colon cancer in acromegaly patients . In 2008These findings provide convincing evidence for a favorable clinical connection between acromegaly and colorectal carcinoma. Having stated that, screening for colon pathologies in acromegaly patients becomes critical. The objectives of screening are to detect dysplasia before it advances to carcinoma, detect carcinoma before clinical symptoms appear, and prevent it from metastasizing. Direct visualization screening using colonoscopy and flexible sigmoidoscopy, and CT colonography are considered as more effective modalities for identifying colon neoplasia . AlternaLimitationsPotential confounding factors for the development of colorectal neoplasia such as age, gender, insulin resistance, circulating insulin levels, diabetes mellitus status, hypertension status, body mass index, high fatty diet, family history, and geographical distribution have not been taken into account in all of the studies presented. According to the studies covered in this article, despite patients with acromegaly having significant morphological alterations, the condition is also a causal factor for colorectal neoplasia such as colorectal polyps and colorectal carcinoma. IGF-1 is responsible for the majority of the pathological changes that take place in acromegaly. Keeping the aforementioned facts in mind, we attempted to emphasize colorectal neoplasia in patients with acromegaly in this review article to raise awareness among physicians to begin screening for colorectal neoplasia using direct visualization methods such as colonoscopy and CT colonography at the moment the patient is diagnosed with acromegaly. When such pathologies are identified at an early pre-malignant stage with the aid of screening methods, grave sequelae such as colonic carcinoma can be prevented with effective management, which has the potential to improve the quality of life and extend the life expectancy of acromegalic patients. We believe that this article can serve as a foundation for researchers to delve deeper into colorectal complications of acromegaly and explore the pathophysiology of this illness in depth. However, we believe that the link between acromegaly and colorectal neoplasia requires further large-scale research studies to be conducted while keeping confounding variables in mind in order to establish appropriate screening and management guidelines.