About 70% of people with osteogenesis imperfecta (OI) experience hearing loss. There is no cure for OI, and therapies to ameliorate hearing loss rely on conventional treatments for auditory impairments in the general population. The success rate of these treatments in the OI population with poor collagenous tissues is still unclear. Here, we conduct a systematic review and meta-analysis on the efficacy of treatments addressing hearing loss in OI. This study conforms to the reporting standards of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). Data sources include published articles in Medline via PubMed, Web of Science, Scopus, and Embase, from their inception to November 2020. Studies included individuals with OI undergoing a hearing loss treatment, having pre- and postoperative objective assessment of hearing function at a specified follow-up length. Our search identified 1144 articles, of which 67 were reviewed at full-text screening. A random-effects meta-analysis was conducted on the selected articles (n = 12) of people with OI that underwent stapes surgery. Success was assessed as the proportion of ears with a postoperative Air–Bone Gap (ABG) ≤ 10 dB. A systematic review was conducted on the remaining articles (n = 13) reporting on other treatments. No meta-analysis was conducted on the latter due to the low number of articles on the topic and the nature of single case studies. The meta-analysis shows that stapes surgeries have a low success rate of 59.08 (95% CI 45.87 to 71.66) in the OI population. The systematic review revealed that cochlear implants, bone-anchored hearing aids, and other implantable hearing aids proved to be feasible, although challenging, in the OI population, with only 2 unsuccessful cases among the 16 reviewed single cases. This analysis of published data on OI shows poor clinical outcomes for the procedures addressing hearing loss. Further studies on hearing loss treatments for OI people are needed. Notably, the mechanisms of hearing loss in OI need to be determined to develop successful and possibly non-invasive treatment strategies. Clinical features are brittle bones with spontaneous fractures, skeletal deformities, joint laxity, blue sclerae, dentinogenesis imperfecta, cardiovascular and respiratory problems, and hearing loss2. Progressive hearing loss affects about 70% of people with OI9, with a prevalence of cases happening already in childhood18. The incidence of hearing loss in OI is notably higher than in the general population, which according to the World Health Organization, is just over 5% of the world’s population19. Interestingly, bone fracture rate decreases after puberty in OI, but hearing loss worsens with age15.Hearing loss is common in people with osteogenesis imperfecta , type II , type III (severe), and type IV (moderate-to-severe), the author reported hearing loss as a common symptom of OI type I and less frequent in OI type IV23. Different observations come from Hartikka et al.7 and Swinnen et al.8, who found no correlation between the mutated gene and OI type and the severity of hearing loss. Instead, da Costa Otavio et al.12 reported normal hearing thresholds in people with OI type I, conductive hearing loss for OI type III, and sensorineural hearing loss for OI type IV. In a multicenter study, Machol et al.24 found an increased prevalence for hearing loss with age in OI type I, while people with OI type III and IV are at higher risk of developing hearing loss already in the first decade of life. The authors also reported a prevalence of sensorineural hearing loss in female individuals with OI24, although hearing loss in OI was previously reported as gender independent21. Disparities between these studies may arise from differences in (i) the methods of assessing hearing loss, and/or (ii) the OI populations  examined, and/or (iii) clinical assessments of OI type: observational in the past and based on genetic analysis in the last decade.Hearing loss in OI is often bilateral29. Common manifestations of conductive hearing loss in OI include a fixed and/or thick stapes footplate47, associated with microcracks accumulation of unclear origin, which may relate to the increased porosity and brittleness of the OI bone48, and that lead to localized bone overgrowth49. Ossicular discontinuity, mainly caused by fractures in the stapes crura, is commonly reported in cases of conductive hearing loss in OI51. Manifestations of sensorineural hearing loss in OI include hyalinization and atrophy of the stria vascularis, hair cell atrophy, and microfractures of the cochlear otic capsule20. Documented otologic microsurgeries in some OI individuals also revealed tectorial membrane distortion and perilymph hemorrhage52. In other OI cases, sclerotic thickening of the cochlear otic capsule and a brittle scutum has been reported53, and demineralization of the bone around the cochlea and vestibule and partial ossification of the basal turn of the cochlea54. In OI, mixed hearing loss often arises with fenestral involvement causing conductive hearing loss and progresses toward the retrofenestral components with age, causing sensorineural hearing loss24. Interestingly, Swinnen et al.49 found an association between whole body low bone mineral density and conductive or mixed hearing loss in people with OI. The OI population suffering from hearing loss also have elevated alkaline phosphatase levels27, an enzyme recently reported to be associated with hearing loss in the general population and suggested to be critical for the diagnosis and progression assessment of auditory impairments55.The mechanisms of hearing loss in OI are still unclear. OI’s most affected anatomical structures include the otic capsule, oval and round windows, stapediovestibular joint, and internal auditory canals40. Otosclerosis is limited to the otic capsule’s endochondral layer, whereas OI involves the endosteum, endochondral layer, and periosteum29. Despite these differences, in the last decades, treatment strategies for hearing loss in OI have been the same as these for the general population's auditory impairments. However, it is unknown how successful they are in the OI population, a disease with no cure. Therefore, this study aims to assess current treatments’ efficacy addressing hearing loss in OI, employing a systematic review and a meta-analysis.Although middle ear lesions reported in OI are similar to those reported in patients with otosclerosis, hearing loss in OI is different: it arises in childhood and is characterized by ossicle atrophies or fractures, and high porosity, and a thicker otic capsulehearing loss, treatment, osteogenesis imperfecta, stapes surgery, stapedectomy, stapedotomy, cochlear implant, hearing aid, drug, bisphosphonates. No language restriction was applied. Reference lists and citations were reviewed to include studies that were missed in the original search.This study conforms to reporting standards of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A systematic review was conducted on the hearing restoration in OI patients after stapes surgeries, cochlear implantation, hearing restoration with bone-anchored hearing aids (BAHA), implantable/non-implantable hearing aids, and drug treatments. The intended population, intervention, comparator, outcome, timing, and settings of this study are summarized in a PICOT table Table . This stWe included publications that addressed hearing loss treatments on individuals with OI and quantitatively and objectively assessed hearing loss before and after treatment at specified time points and follow-up lengths. The lack of auditory assessment, no specified length of follow-up, averaged results for all the cohort of people considered, and mixed data for general and the OI populations were reasons for exclusion of the study. Reports counting the same patients twice were also excluded. Furthermore, because this study aims to determine the success of the primary intervention, studies reporting on revision cases for more than 15% of their cohort were excluded. Any article deviating from the objective of this study was rejected..Two authors searched and screened the included studies, and records were noted in an excel sheet. Duplicated studies were identified and removed. Consequently, abstracts were reviewed, and those deviated from the study’s objective were excluded. The remaining manuscripts were reviewed in full text and included in the study if they complied the inclusion criteria. Disagreements among researchers were resolved through consensus or third-party adjudication. Data about treatment strategy, population characteristics, outcomes of interest, and length of follow-up were extracted. One person performed data collection while a second person reviewed the extracted data. Data was then analyzed and divided to conduct: (1) a meta-analysis on the efficacy of stapes surgery in OI and (2) a systematic review on the rest of the treatments for hearing loss in OI. The studies included in the systematic review were single study cases with 1–3 individuals. They did not allow for a meta-analysis to be conducted due to the small total number of individuals considered and the lack of data about treatment efficacy56, according to the analyzed type of study. Namely, the NIH quality assessment tools for (1) Before-After (Pre-Post) Studies With No Control Group were used for the studies in the meta-analysis; (2) Case Series studies were used for the studies in the systematic review; (3) Observational Cohort and Cross-Sectional Studies were used for the two observational studies reporting on the effect of bisphosphonates on hearing function57 as in their cohort bisphosphonate treatments were not intended as a first treatment for hearing loss in OI.The quality of the articles included in this meta-analysis and systematic review was determined by following three quality assessment tools from The National Institutes of HealthInclusion criteria comprised published studies on people with OI who have been diagnosed with hearing loss using pure tone audiometry and underwent primary stapes surgery  and have been followed up in the clinic at specified times. Excluded publications were articles without information on stapes intervention, studies without pure tone audiometry results, not reporting postoperative audiometry outcomes, articles performing revision surgeries in > 15% of their cohort, studies presenting solely graphical data, and reporting mean values for the entire cohort. Studies that reported the Air–Bone Gap (ABG) value as a mean for the entire cohort rather than patient-specific ABG values or the percentage of the subjects with an ABG ≤ 10 dB, were also excluded from the selection.58.According to the aforementioned screening process, data was extracted from the selected articles for meta-analysis. The database included article characteristics , treatment strategy , pure-tone audiometry results , population characteristics  and length of follow-up. The level of evidence of each study included in the meta-analysis was evaluated through Oxford Centre for Evidence-Based Medicine criteriahttps://www.medcalc.org; 2020), and a proportion meta-analysis was conducted on the efficacy of stapes surgeries. Because closure of the ABG within 10 dB or less is considered a successful outcome of stapes surgeries in the literature59, the efficacy of stapes surgeries was quantified as the proportion of ears having an ABG ≤ 10 dB. An effect size (proportion of successful cases) was calculated for each study with its corresponding 95% confidence interval (CI).Statistic calculus and analysis were conducted using MedCalc 19.2.3 , quantified using 61 and Begg’s rank test62 were used to detect possible publication bias using MedCalc. A low P-value (< 0.05) indicates publication bias in both tests. Funnel plots were also created to detect bias in the meta-analysis. Asymmetry of the funnel plots was evaluated considering that heterogeneity factors could have an effect63.Egger’s testThe literature search identified 1144 studies, of which 946 duplicates were excluded. Among the remaining 198 studies, 131 were excluded at the abstract level, and 67 articles were reviewed at full text. Twelve articles met the inclusion criteria and were included for meta-analysis, whereas 13 were included for systematic review  and long-term (> 12 months) audiometry values were extracted. Intraoperative findings encountered in these 12 reports are reported in Table The quality assessment of the articles included in the meta-analysis is reported in Supplementary Table Twelve studies assessed the outcomes of primary stapes surgeries using pure-tone audiometry in individuals with OI. All of them included the proportion of ears showing an ABG ≤ 10 dB and length of follow-up. Long-term results showed an evident reduction in individuals’ participation during follow-up, introducing biases for those measurements. Thus, we only considered short-term effects within 12 months) for the meta-analysis, and a random-effects model meta-analysis was conducted. With a total sample size of 337 cases within the 12 manuscripts here considered, our results show that stapes surgeries have a short-term success rate of 59.08 (95% CI 45.87 to 71.66) in the OI population  and Regarding the risk of bias within the meta-analysis, Both Egger’s test and Begg’s test show high P-values , indicating low to no risk of bias across studies. Also, the symmetry of the funnel plots in Fig. The quality assessment of the studies included for systematic review can be found in Tables 64 and Marfatia et al.54, in which the individuals were 6 and 14 years old, respectively, at the time of surgery.A total of nine studies reported outcomes on 11 cases of unilateral cochlear implantations in OI individuals. Table 65. In all cases, the implantation was challenging because of ear hypervascularization, severe demineralization of the otic capsule, proliferation of the round window niche, and lack of anatomical landmarks typical of the OI population66. A high incidence of facial nerve stimulation after cochlear implantation was also common in people with OI67, and in three cases it was controlled through programming strategies67.Among the above-identified articles, cochlear implantation in people with OI showed improvement in speech perception scores in the short term (≤ 12 months) in 10 out of 11 reported cases. A non-successful outcome was related to a placement failure of the electrode array68. Despite the brittleness of the OI bone, this single case was successful with free field audiometry showing a mean improvement of about 45 dB . Improvement was also observed in the speech audiometry results when fitting the bone-anchored hearing aid, with approximately a 40 dB hearing function difference. Implant osteointegration was reported, given by implant stability quotient values measured by resonance frequency analysis in four cardinal points of the abutment68.Only one study described the efficacy of BAHA in an individual (aged 45) suffering from OI type III hearing loss in a single ear65 reported no benefit in a person with OI type I fitted with an implantable hearing aid, in which the transducer was placed at the round window. Kontorinis et al.69, on the other hand, reported three successful cases in two people with OI type I, fitted with implantable hearing aids. In these two people, the transducer was attached to the long process of the incus in the proximity of the incudostapedial joint, and stapedotomy was performed. They reported a mean preoperative bone conduction and air-conduction threshold of 47.1 dB (range 40–55 dB) and 79 dB (range 60–90 dB), respectively, and postoperative bone conduction and air conduction threshold of 45 dB (range 36.3–50 dB) and 42.1 dB (range 32.5–51.3 dB), respectively.Sainz et al.70. However, no study was found reporting data about their efficacy.Hearing aids are widely used in the OI population until they show no longer benefit caused by the progressing hearing loss57. The study of Ting and Zacharin13 included children treated with either pamidronate  or zoledronic acid (intravenous 0.05 mg/kg 4 monthly), for at least 2 years. Hearing function was assessed using tympanometry and pure tone audiometry at 0.5, 1, 2, and 4 kHz13. The study by Brodd et al.57 included adults with OI who received either intravenous injections of pamidronate or weekly oral alendronate tablets and supplements of calcium and vitamin D for at least 3 years. Pure tone audiometry at 0.5, 1, 2, 3 and 4 kHz was conducted to assess hearing57. The results showed that bisphosphonates have non-significant effects on the hearing of adults with OI. In contrast, Ting and Zacharin13 reported that the incidence of hearing loss was substantially lower in children treated with bisphosphonates for their bone fragility, compared to the untreated subjects from their previous studies. The authors13 suggested that treatment with bisphosphonates might reduce or halt the natural progression of hearing loss in OI. The limitation of their study is that they only assessed hearing in 4 of their 36 patients after treatment13.Two studies reported the effects of bisphosphonates on the hearing function in OI69. Finally, drug treatments for hearing loss in OI are not yet used. The lack of knowledge on the disease mechanisms and progress affecting the inner and middle ear disfunction in OI plays a major role on the absence of suitable treatments for hearing loss in OI.This study examined the efficacy of current treatment strategies to ameliorate hearing loss in OI. Our results show that treatments addressing hearing loss in OI rely mostly on conventional treatments for auditory impairments in the general population. Together with hearing aids and cochlear implants, stapes implants are widely used in OI. Nevertheless, their efficacy is limited, and their success rate is impacted by the bone fragility and high vascularity typical of the disease. Rare is the use of BAHA and implantable hearing aids in OI50 make surgeries challenging for the OI population42 and likely to require revisions71. Our meta-analysis heterogeneity values showed that the proportion of ears having an ABG ≤ 10 dB is a highly variable effect across studies with people with OI. Factors influencing this variation could not be determined here. Still, they can be attributed to the different OI types included in the cohort of each study, age and gender of the individuals involved, and the ability of the surgeon performing the interventions. The variability in outcome among the studies considered here may also be attributed to absence of the definition of hearing loss in the included studies. For our meta-analysis we assumed that studies defined hearing loss as thresholds elevations of 15 dB or 20 dB51. A previous study reported similar outcomes and intraoperative findings for different OI types35. However, we could not assess these variables’ effect due to a lack of reported data. Hence, we suggest that studies publish detailed data and distinguished outcomes for different OI types. Inconsistency of follow-up time was observed across studies. Here, we considered only a follow-up time that was in the range of months for all the studies, so that this factor has little to no effect on the meta-analysis results. For stapes surgery, small deterioration of the postoperative outcomes is expected over the years51, and our comparisons are made in a range of months. Furthermore, the loss of follow-up in some of the stapes surgery studies in OI limited our study to the use of only outcomes for short-term follow-up. Long-term follow-up and data on revision could give a better prospect on the actual duration of the efficacy of stapes surgery in OI. According to Skarżyński et al.71, stapes surgeries in OI have an elevated risk of requiring revision surgeries. The brittle nature of OI bone and common intraoperative complications reported in the literature for stapes surgery in individuals with OI . Challenges and complications were reported associated with the insertion of the electrode array in individuals with OI8, also reported the use of BAHA in people with OI, but no data was reported about their efficacy. Implantable hearing aids have shown good outcomes in the few reported cases and might serve as a solution for hearing loss in the OI population. Anyhow, further studies are needed to strengthen the results on its efficacy and feasibility. No study was found on the efficacy of hearing aids in the OI population, although they are widely used due to their cheap cost.The single case reporting on the BAHA implant in a person with OI claims that OI’s characteristic brittle bone is not a constraint for selected cases. Swinnen et al.75. While bisphosphonates are used to increase bone quantity in OI, it is not clear whether they also reduce hearing loss. Because of their wide use in the OI population, future studies should investigate their effect on the audiological performances of people with OI.Recently, bisphosphonates, a group of antiresorptive drugs for bone and the standard-of-care treatment for severe OI, have been suggested to be a treatment of hearing loss by stabilizing sensorineural hearing loss in cochlear otosclerosisThe lack of knowledge of the mechanisms inducing hearing loss in OI constitutes a major limitation to the use of effective treatments. Clinical observational studies are needed to further understand the evolution of hearing loss in the OI population. Furthermore, preclinical studies using animal models of OI suffering from hearing loss are required to understand the etiology and mechanisms of hearing loss, and to develop new targeted treatments to prevent auditory impairments in OI. Hearing function as well as ear biomechanics and quality of collagenous tissues at multiple length scales should be investigated with multidisciplinary approaches. Therapies for hearing loss in OI should be further investigated for their direct and side effects in animal models. Finally, clinical trials can be conducted to investigate efficacy of a single or combination of treatments, for both hearing loss and bone fragility, in the OI population.This systematic review and meta-analysis on the current treatments of hearing loss in OI shows that the efficacy of stapes surgeries has a low 59.08% success rate, and the other treatments addressing hearing loss in OI  showed to be feasible and successful in ameliorating hearing loss in the OI population in the very few reported single cases. This study emphasizes the need of further research to understand the mechanism(s) of OI leading to hearing loss and to advance current and new treatment strategies to prevent or reduce hearing loss in OI.Supplementary Table S1.


Children with LVAS can develop a severe sensorineural hearing loss early in childhood, but they can be rehabilitated with hearing aids to continue their regular studies and to have a normal life. The problem is that they can deteriorate their hearing capacity, and at this point a cochlear implant can be used to preserve their hearing skills and vocalization.to evaluate the hearing skills of 3 children with LVAS referred to cochlear implants.retrospective study based on medical charts' review.Speech recognition in open field: patient 1, 80%; patient 2, 87.5%; patient 3, 4 %.Children with LVAS are considered good candidates for Cochlear implant surgery by the most important centers of the world because most of them can develop good speech recognition, providing them a good social life. The vestibular aqueduct is a bony canal within the temporal bone, which goes from the medial wall of the inner ear vestibule all the way to the posterior surface of the petrous bone pyramid. The endolymphatic duct crosses the vestibular aqueduct and ends in the endolymphatic sac. During embryogenesis, the vestibular aqueduct starts as a long and narrow vestibular diverticulum. A development defect before the diverticulum starts to narrow, on the fifth week of gestation, results in an enlarged vestibular aqueduct.,,In 1978, Valvassori and Clemis identified 50 cases of enlarged vestibular aqueduct in a retrospective study of 3,700 patients who were submitted to temporal bone CT scan in order to study inner ear structures. A vestibular aqueduct is considered enlarged when its antero-posterior diameter is equal to 1.5mm. These authors were the first to use the definition of Enlarged Vestibular Aqueduct Syndrome (EVAS). Since this time, many studies were carried out in order to better characterize the syndrome and found that 59% to 94% of the cases were bilateral; 60% to 66% of the patients are female, and sensorineural hearing loss is progressive in 46% to 65% of the patients.6The enlarged vestibular aqueduct may happen as an isolated anomaly or in association with other inner ear malformations. The most common is the enlargement of the horizontal semi-circular canal, 60% to 66%, and cochlear hypoplasia, 28%,,The pathophysiology of this sensorineural hearing loss caused by an enlargement of the vestibular aqueduct is still unknown. Two things may happen, the first suggests a rupture of the labyrinthine membrane or perilymphatic fistula, resulting in a direct transmission of the cerebro-spinal fluid pressure to the middle cochlear turn through the endolymphatic duct and enlarged vestibular aqueduct, and the second suggests a hyperosmolar fluid reflux to the cochlea coming from the endolymphatic sac. More recent studies have mapped the hearing loss associated with the enlarged vestibular aqueduct in the region of chromosome 7q31, however, its clinical meaning still requires more investigation.Children with EVAS may have moderate to severe hearing deficiencies during their early stages of childhood, however their residual hearing allows them to develop oral language with conventional hearing aids and may be completely integrated to regular school conditions. Nonetheless, these children have a worsening in their hearing skills with time and cochlear implants are being offered as an option to keep their hearing and oral communication skills in proper levelsThis study reports the experience of treating 3 patients with enlarged aqueduct syndrome with cochlear implants.This study was analyzed and approved by the Ethics in Research with Human Beings Committee of the HRAC/USP under protocol # 158/2007-SVAPEPE-CEP.We carried out a retrospective study to identify all the patients using cochlear implants in our population and were pre-operatively diagnosed with enlarged vestibular aqueducts. So far, 504 cochlear implant surgeries have been performed and only 3 (0.6%) of these patients were diagnosed with enlarged vestibular aqueduct through CT scan and MRI, a much lower number when compared to what has been found in other large centers.Radiology exams were carried out under sedation with 20% chloral hydrate. CT scans were carried out in a spiral Elscint Twin device, with 0.5mm axial sections, with later axial plane reconstruction .Figure 1The vestibular aqueduct was considered enlarged when its antero-posterior diameter was equal to or greater than 1.5mm .Figure 2MRI exams were carried out in Phillips devices with 1.0 Tesla magnetic fields, following the protocol for patients eligible to receive the cochlear implant:FLAIR sequence for the encephalon.Turbo SpinEcho (TSE) sequence, axial plane, T1 weighed images of the posterior fossa Figure 3BTSE sequence, axial plane, T2 weighed images .Figure 4MIP sequence, with submillimeter cross-sections (0.6mm) in the axial and sagittal planes, T2 weighed images, to evaluate the membranous labyrinth and the VII and VIII cranial nerves.MIP 3D reconstruction .Figure 6The cochlear implant was done through a transmastoid approach, with posterior tympanotomy and a 2.0mm cochleostomy made in a right angle with the stapes tendon. We had no gusher during cochleostomy, however there was some pulsating oozing of perilymphatic/cerebro-spinal fluid. In all cases the active electrodes were inserted without difficulties, we achieved complete insertion, and the cochlea was sealed with fragments of temporal muscle fascia.Patient number 1 was male, pre-lingual, and was implanted at 6 years and 5 months of age on the left side.He received a Nucleus cochlear implant, model CI24RST . He had an enlarged vestibular aqueduct and hyperplasic cochlea in the image exam.Patient 02 was female, post-lingual, and was implanted at the age of 5 years and 9 months, on the right side. She received a Nucleus, CI24RST  implant, and did not have other malformations seen in her image exams.Patient 03 was also a female, pre-lingual, and was implanted at 6 years and 1 month of age, and she was reimplanted three years later, because of a failure in the internal device. She was implanted and reimplanted on the right side and received a MedEl, model C40+ short  cochlear implant both times, and she did not have other malformations visible in her image exams.All patients used conventional hearing aids for at least 6 months after the implant and had bilateral enlarged vestibular aqueduct.Audiometric evaluation for each patient included pure tone recordings without the hearing aid, 6 months of hearing aid use and 1 year after the implant .Table 1ETests from Delgado (8), GASP (9) and Ling's sounds (10) were used to assess speech perception.Patient # 1 had 80% word recognition, in open settings, patient # 2 had 87.5% in open settings and patient # 3 had word recognition of 4% in open settings, Ling's sound detection was equal to 100%, with phoneme /a/ discrimination equal to 50%, phoneme /i/ equal to 0% and phoneme /u/ equal to 0% in a closed setting.,The Enlarged Vestibular Aqueduct Syndrome (EVAS) represented a treatment challenge for physicians who treated these patients, because of the lack of a protocol able to efficiently prevent the progression of hearing loss in them. Conservative measures such as education to avoid head injuries and barotrauma or pressure fluctuations and treatment with steroids in cases of sudden hearing loss have yielded some success. Endolymphatic sac surgeries were carried out in patients with progressive congenital impairment, however were not considered efficient. Endolymphatic sac obliteration was also described by Wilson et al. as a means to control the progressive hearing loss; however, its results could not be repeated in other studiesSome few studies have considered the use of a cochlear implant as an option for the patient with EVAS, if bearers of severe-profound or profound sensorineural hearing loss. Harker et al. reported 5 pediatric patients with EVAS, who were implanted and presented excellent results in speech detection. He did not find gusher in any of the surgical procedures. Bent et al. reported a case of 10 patients with EVAS, who received cochlear implant. They noticed a small perilymph pulsating oozing caused by cochleostomy in 5 patients, which were easily controlled with the use of temporal muscle fascia. Seven of the eight children who had already been implanted some time before improved in word recognition in an open setting. Myamoto et al. implanted 23 patients with EVAS, 9 children and 14 adults. He reported gusher in 5 of these patients, however there were no difficulties in inserting electrodes in these patients and the cochleostomy was sealed with a fragment of temporal muscle fascia. This study also found benefits for patients with EVASThese results, as well as our experience, consider the cochlear implant surgery to be safe in patients with enlarged vestibular aqueduct and a complete insertion of electrodes is doable. Despite the oozing of perilymph during cochleostomy being somewhat common, it is easily controlled by sealing it with a fragment of temporal muscle fascia. Searching for the association of other malformations with the enlarged vestibular aqueduct and the diameter of the vestibular aqueduct were not relevant in predicting gusher during surgery.,In regards of developing speech skills, there is a marked difference between the many types of inner ear malformations. Unanimously, all cochlear implant centers that have performed surgery in children with inner ear malformations report that those with cochlear dysplasia, enlarged vestibular aqueduct and dilated vestibule, in other words, Mondini's malformation and, especially, those with EVAS are the ones that have the greatest gains in their development with cochlear implants in terms of word recognition and speechBased on the audiometric evaluation of these patients and their speech perception, we can see that these are children with great potential to develop speech perception in an open setting, phonemes and phrases, and this allows them to go to regular schools and have a normal social development. When we notice a low development, we must bear in mind that the enlarged vestibular aqueduct is present in other syndromes such as the Pendred and the Otobrachiorenal syndromesThe major doubt still lies in defining the ideal time for surgery, because hearing loss can behave in different ways such as progressive, sudden or fluctuating, the assessment of these patients require a thorough follow upPatients with enlarged vestibular aqueduct are considered eligible for receiving cochlear implants by the major cochlear implant centers in the world, because most of them develop good audiometric and speech recognition performances, and this provides them better social participation.Nonetheless, we stress that it is important, besides image studies, to investigate the presence of other syndromes that may follow that of the enlarged vestibular aqueduct.


Hearing acuity, central auditory processing and cognition contribute to the speech recognition difficulty experienced by older adults. Therefore, quantifying the contribution of these factors on speech recognition problem is important in order to formulate a holistic and effective rehabilitation.To examine the relative contributions of auditory functioning and cognition status to speech recognition in quiet and in noise.We measured speech recognition in quiet and in composite noise using the Malay Hearing in noise test on 72 native Malay speakers (60–82 years) older adults with normal to mild hearing loss. Auditory function included pure tone audiogram, gaps-in-noise, and dichotic digit tests. Cognitive function was assessed using the Malay Montreal cognitive assessment.r2 = 0.499). On the other hand, high frequency average, Malay Montreal cognitive assessment and dichotic digit tests contributed significantly to speech recognition in noise . Whereas the better ear high frequency average primarily measured the speech recognition in quiet, the speech recognition in noise was mainly measured by cognitive function.Linear regression analyses using backward elimination technique revealed that had the better ear four frequency average (0.5–4 kHz) (4FA), high frequency average and Malay Montreal cognitive assessment attributed to speech perception in quiet (total These findings highlight the fact that besides hearing sensitivity, cognition plays an important role in speech recognition ability among older adults, especially in noisy environments. Therefore, in addition to hearing aids, rehabilitation, which trains cognition, may have a role in improving speech recognition in noise ability of older adults. Following a speech conversation in a noisy environment is hard, especially among older adults with and without hearing impairment.In addition to peripheral hearing loss, ageing is often accompanied by reduced sound processing efficiency due to degeneration of central auditory pathwayThe roles of central auditory and cognitive factors in understanding speech in noise have been extensively studied in the past decades.Another central auditory processing function which declines with age is dichotic listening. Dichotic listening is a challenging task in that a listener is required to cope with competing sound signals presented to both ears simultaneously. A study investigated the influence of age attentional control of bottom-up, stimulus driven lateral effect in younger and older adults.The influence of cognition on speech understanding in noise has been vastly studied and established.Given that difficulties listening in noise is common and continue to decline among older adults, and the fact that hearing loss alone does not always explain these problems, it is important that we examine the relative contributions of peripheral auditory, central auditory and cognitive processes to speech recognition. Knowing the magnitude of the effects of these processes is crucial in developing a more comprehensive management plan of hearing loss in older adults. Therefore, this study is aimed to determine the relative contribution of auditory and cognitive functions on speech recognition in older adults with normal to mild hearing loss. This study is novel in a way. Firstly, while many studies have examined the contribution of central auditory processing on speech recognition performance among older adults, very few have included dichotic listening test. We included gaps-in-noise and dichotic listening test as measures of central auditory processing in this study. Specifically, we view the inclusion of dichotic listening test as important because some studies suggest the potential of dichotic listening training in improving speech recognition.A total of 72 participants participated in this study. To be included participants must be 60 years old or more, right handed, native Malay speakers had no history of stroke, head injury, ear surgery, psychiatric problem or dementia. Additionally, participants must have normal middle ear function based on tympanometry and symmetrical hearing level with normal hearing or mild hearing loss as indicated by Pure Tone Average (PTA) for 0.5, 1, 2 and 4 kHz of 40 dB HL or less in the better ear. Symmetrical hearing threshold was defined as difference between the PTA (0.5–4.0 kHz) of both ears of no greater than 10 dB. The tests were spread into two sessions, which lasted about one hour each. The experimental protocol and procedures in this study were approved by the Universiti Kebangsaan Malaysia Research Ethics Committee . Informed consent was obtained before data collection.Pure-Tone Audiometry (PTA) was conducted by a trained audiologist in a sound treated booth, using standard TDH-39 earphones and a Madsen OB822 audiometer (Madsen Electronics Itera 2). Air conduction (AC) thresholds for each ear were measured for frequencies of 0.5, 1.0, 2.0, 4.0, and 8.0 kHz. Bone Conduction (BC) was evaluated whenever AC thresholds were greater than 20 dB HL for frequencies of 0.5, 1.0, 2.0 and 4.0 Hz. Masking for air and bone conduction thresholds were performed when indicated. The four-frequency pure tone average (4FA) was calculated for frequencies of 0.5, 1.0, 2.0 and 4.0 kHz. High frequency average (HFA) was based on frequencies 4 and 8 kHz. Normal and mild hearing loss were defined as follows: no impairment, PTA ≤25 dB HL and mild, PTA 26–40 dB HL.Tympanometry was conducted on both ears using an Interacoustic Titan tympanometer. A normal tympanogram was defined as static admittance of 0.2–1.5 mmho and tympanometric width of 35–125 dapa.DDT was conducted using the Malay double dichotic digits test.The GIN test was administered and scored according to the set criteria by Musiek et al.The speech in noise test was conducted in a sound booth using the Malay version of Hearing in Noise Test (MyHINT).The HINT was conducted in four different conditions: (1) In quiet (HINT Q), (2) HINT Noise Front (HINT NF), (3) HINT Noise Right (HINT NR), and HINT Noise Left (HINT NL). In all test conditions, speech was presented from the front. In noise conditions, the noise level was fixed at 65 dB A. RTS was calculated based on the average presentation level of the 5th through the 20th sentences and the level at which the 21st sentence would be presented.In this study, HINT (Q) and HINT (composite), a score often used as a descriptor of noise conditionsThe global cognitive function was assessed using the Malay version of Montreal cognitive assessment,Data was analyzed using the Statistical package for the social sciences version 22. Descriptive analyses were performed on demographic data, auditory function tests and MoCA. The associations between measures on HINT test with age, peripheral auditory, central auditory tests and MoCA were assessed using Pearson Correlation test. Finally, multiple linear regression analyses were used to determine relative contributions of auditory performance, and global cognitive performance and HINT measures.A total of 72 individuals, 18 males and 54 females between 60 and 82 years old  participated. We performed multiple linear regression analyses to determine how much hearing acuity, central auditory tests and MoCA attributed to the variations of each of the HINT outcomes. To examine potential cases of collinearity between predictor variables, we performed a diagnostic collinearity test using a linear regression analysis. No collinearities were observed, with variance inflation factor values less than 2. Thus, all predictor variables were included in the regression analyses.p value at each step, until only variables with p < 0.1 remained in the model. The final models are shown in Multiple linear regression analyses were performed using backward elimination method. The predictor variables were excluded stepwise, removing the variable with the highest F(4.67) = 18.706, p < 0.001. The three variables accounted to 49.9% of the variance. The proportion of variance in RTS (Quiet) uniquely explained by these variables, as indexed by the squared semi-partial correlations (part r2) were 29.2% by the BE HFA, 10.9% by the BE 4FA, and 5.7% by MoCA. The positive beta coefficient for the two hearing averages and negative beta coefficient for MoCA indicate that HINT (Q) performance worsened as the hearing averages increased and the MoCA reduced. Individual differences in BE HFA, DDT (REA), and MoCA together accounted for 30.7% of the HINT (Composite) variance, F(3.68) = 11.467, p < 0.001. MoCA uniquely accounted to 18.5% of the variance, followed by BE HFA (12.4%) and DDT (REA) (8.2%). Lower MoCA, greater BE HFA and DDT (REA) yielded worse HINT (COMPOSITE) performance.The results indicated that HINT (Q) was best predicted by BE 4FA, BE HFA and MoCA, In the present study, which involved older adult participants with normal and with mild hearing loss at 4FA, hearing acuity at both low to mid frequencies as well as at high frequencies significantly contributed to the variance of HINT in quiet. The 4FA and HFA uniquely accounted for 10.9% and 29.2% of the variance of HINT (Q), respectively. These results corroborated the findings of previous research which explained the importance of speech spectrum audibility in speech recognition performance.34The importance of high frequency hearing acuity in speech recognition in quiet, especially in older adults, has been well established. Articulation index theory predicts that individuals with sloping high frequency hearing loss such as in presbycusis will experience difficulty listening to speech at conversational level due to inaudibility of high frequency speech sounds.40The importance of high frequency hearing in speech intelligibility in noise has also been well documented. For example, a recent study indicated that elderly listeners with better high frequency hearing in the region between 6 and 10 kHz had greater spatial release from masking resulting in better speech recognition when speech and noise are spatially separated.Although most prior studies have observed strong correlations between speech recognition in both quiet and noise and hearing thresholds up to 4 kHz,GIN and DDT, were included as measures of central auditory processing in the present study. Generally, our findings revealed that GIN did not contribute to any of the HINT outcomes. In contrast, the DDT (REA) contributed significantly to the variances of HINT (COMPOSITE), albeit minimally (8.2%). The lack of significant influence of GIN on HINT outcomes fits well with those of the previous studiesThere have been limited studies which examined the relationship between dichotic listening and speech recognition performance. A study which examined the relationship between the two measures found a strong negative correlation between dichotic score and speech recognition in noise.The cognitive function as indexed by MoCA uniquely contributed to 5.7% and 18.5% of the variances of the HINT (Q) and HINT (Composite), respectively. The greater contribution of MoCA on HINT (Composite) than HINT (Q) is expected because listening to speech in quiet relies more on speech audibility and is less cognitively taxing. During speech recognition process, speech information is continuously compared with the information stored in long-term memory. If these information match, speech processing and understanding on higher level will occur implicitly and effortlessly.This study has a few limitations. First, the use of MoCA rather than more specific neuropsychological test battery make it impossible to ascertain which cognitive domains contribute to the speech recognition performance. MoCA as a single measure of cognitive function has, however, been use in previous studies which examined the influence of cognitive functions on speech understanding by older adults.This study examined the contributions of hearing level, measures of central auditory processing, and cognitive status on speech recognition performance in quiet and in noise. Our findings revealed that BE 4FA, BE HFA and cognition were the significant predictors and accounted for about 50% of the variance of speech recognition in quiet. In contrast, HFA, cognitive status as measured by MoCA and REA significantly predicted about 30% of the variance of speech recognition in noise condition. While high frequency hearing was the primary predictor for speech recognition in quiet, MoCA score contributed more than high frequency hearing to the variance of speech recognition in noise. These findings suggest that rehabilitation that geared towards improving cognitive function could help in alleviating some of speech recognition difficulties experienced by older adults, especially, in noisy environment. Additionally, the fact that the included predictors explain only about 20–40% of HINT performance, suggests that there are other relevant predictors that have not been covered in the present study.This study was funded by the Malaysian Ministry of Education research grant (LRGS/BU/2012/UKM-UKM/K/02).The authors declare no conflicts of interest.


Noise-induced hearing loss (NIHL) is defined as the sensorineural hearing loss caused by acute acoustic trauma or chronic exposure to high-intensity noises. Exposure to noises can lead to irreversible damage to the inner ear and, consequently, to a permanent shift of the hearing threshold. Police officers are particularly at risk of acute or chronic hearing damages. The aim of this study is to evaluate the hearing loss of police officers in relation to the occupational risk factors and clinical-anamnestic characteristics by collecting and analyzing existing data and evidence available in public databases.A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses group (PRISMA). Studies were included if they met inclusion and exclusion criteria. Study selection, data extraction, and quality assessment were conducted independently by two researchers. Our initial literature search yielded 29 peer-reviewed articles. Out of 29 papers, only 10 were included in the review, after inclusion and exclusion criteria were applied the.Hypertension, smoking and alcohol intake significantly affect hearing performance. In addition, a history of acoustic trauma, use of ototoxic drugs, exposure to noise in leisure-time activities and failure to use ear protectors are often found in a fair number of subjects. NIHL is also related to the age of the subjects as well as the extent and duration of noise exposure. Furthermore, NIHL is also influenced by shooting practice sessions police officers are required to undertake as well as by the chronic exposure to traffic noise, especially in motorcycle police officers. The World Health Organization (WHO) has stated that approximately 466 million people worldwide have disabling hearing loss and that this number will increase to approximately 900 million people in 2050, affecting more than 5% of the world's population . MoreoveThe Ministry of Health reported that in 2019 in Italy there were about 7 million people suffering from hearing loss, corresponding to about 11.7% of the population throughout the national territory . The WHO states that the most common causes of hearing loss worldwide include genetic causes, birth complications, infectious diseases, ear infections, the use of ototoxic drugs and aging . In the Noise-induced hearing loss (NIHL) represents sensorineural hearing loss caused by acute acoustic trauma or chronic exposure to high-intensity noise . Today many people work in particularly noisy environments because of their profession: bus drivers, airplane pilots, military personnel and in general all people who work in outdoor environments -9. Exposure to noise can lead to a temporary shift in the hearing threshold on audiometry which would resolve within approximately two weeks; a continuous exposure to noise could instead lead to irreversible damage to the inner ear and, consequently, to a permanent shift of the hearing threshold ,11. In sIn addition to the above-mentioned professional categories police officers are also at risk, of acute or chronic hearing damages. Some of them are particularly exposed sources of noise, such as those working carried in the dog units and on duty in the streets and circulating in the streets with motorcycles ,16. FurtWe conducted a systematic review aiming to evaluate the hearing loss of police officers in relation to the occupational risk factors and clinical-anamnestic characteristics.This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses group (PRISMA) by selecting data using the PRISMA NMA Checklist .A systematic review was performed of public databases  by using a search strategy that included five keywords: noise AND induced AND hearing AND loss AND policemen. We included all the studies regardless publication date or publication status until 28 February 2021. Articles published in languages other than English were excluded. Studies were included if they met the following criteria: 1) type of participants: studies on police officers of all ages and ethnicity.2) type of clinical-instrumental assessment: studies with an analysis of the auditory assessment (audiometry) of patients in relation to the hearing-loss risk factors and characteristics.3) types of study: randomized controlled trials (RCT), nonrandomized controlled trials (NRCT), cohort studies, before-and-after studies (including before-and-after comparison case studies), case-control studies.Studies with the below features were excluded:1) type of participants: patients who do not work as police officers.2) type of clinical-instrumental assessment: studies in which patients underwent to clinical and instrumental assessment other than the ones listed in the inclusion criteria.3) types of study: case reports, narrative reviews.Data were extracted by two researchers independently; any disagreement about data extraction was discussed until a consensus was reached. The results of the systematic review were synthetized, classified and analyzed according to different individual variables, the study characteristics and results. The individual variables considered are the following: NIHL, noise exposure in leisure time, a history of occupational noise exposure, acoustic trauma, a family history of hearing loss, use of ototoxic drugs or exposure to chemicals, use of ear protectors, a history of ENT and/or non-ENT diseases, a history of upper airways diseases, pre-existing condition of hearing loss, transmission-type hearing loss, smoking, alcohol abuse, diabetes, hypertension, hypercholestero- lemia, fullness, tinnitus, dizziness.The articles selected after the primary search were included/excluded by screening the title and abstract of each study and applying the inclusion/exclusion criteria. We removed duplicates from the primary search. We confirmed the remaining studies and validated them.Our initial literature search yielded 29 peer-reviewed articles. After applying the inclusion and exclusion criteria, we retained 10 studies to be included in the systematic review. We then extracted the data for each individual variable from the result section of the selected articles.Three studies ,17,20. HSmoking was found in four studies for a total of 751 subjects ,21,22,26NIHL is defined as a sensorineural hearing loss due to exposure to acute or chronic high-intensity noises. Audiometry shows a hearing loss at high frequencies , which defines the hearing loss typical of this hearing profile.Police officers are subjected to various occupational risks, injuries and diseases of various kinds . The studies included in this review analysed the hearing loss of police officers and the potential impact of noises they are exposed to, due to their occupation, in relation to different clinical-anamnestic characteristics.Some of these studies confirmed a varying degree of NIHL in many subjects.In particular, Win et al. evaluated the hearing performance of 365 police officers. The prevalence of NIHL was 34.2%, with a higher prevalence in males (37.7%), compared to females (23.9%) . A similChauhan et al evaluated 88 traffic police officers by using smartphone-based audiometric testing (software Hearing Test TM). Among the participants, 80 subjects had NIHL  . RajendeIn one study, Win et al. found that participants had mild NIHL in 93% of the cases, moderate and severe NIHL in 3.5% of the cases . The stuWin et al. confirmed a significant association between NIHL and hypertension  and, overall, how other variables  may contribute significantly to NIHL . In one In one study, Shrestha et al. found that 26 participants 23.6%) had tinnitus and 39 (35.5%) had “blocked sensation” in the ear . Malowsk.6% had tIn particular, after the first study session, nine subjects (45%) experienced tinnitus, but none of them complained dizziness or vertigo. However, in the second phase of the study10 years after the first observation, three subjects 25%) reported tinnitus and only 1 subject (8%) had episodes of dizziness without rotatory vertigo . These d% reporteThe literature shows how this symptom is often reported by those suffering from hearing loss associated with inner ear disorders ,36. AudiNIHL is a pathological condition that affects several occupational categories. This review highlights the impact that the environmental or occupational noise to which police officers are exposed to, can have on the function of the inner ear leading to significant alterations and resulting in transient or permanent hearing loss.There are many factors that can lead to this condition: hypertension, smoking and alcohol intake significantly affect hearing performance. In addition, a history of acoustic trauma, the use of ototoxic drugs, exposure to noise during leisure time and the failure to use ear protectors are often found in a fair number of subjects.NIHL is also related to the age of the subjects as well as the extent and duration of noise exposure. Furthermore, hearing loss is influenced by shooting practice sessions police officers are required to undertake as well as by the chronic environmental exposure to traffic noise, especially in motorcycle police officers.A conscious use of ear protectors, both internal inserts and external headphones, prevention and education programs for police personnel as well as close audiological and occupational clinical surveillance of these subjects, could contribute to greatly reduce this unresolved problem strongly impacting on the health of police officers.All authors have no conflict of interest to declare.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.


Purpose: To establish and validate a model to determine the occurrence risk of colorectal ademomatous polyps.Methods: A large cohort of 3576 eligible participants who were treated in the Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University from June 2019 to December 2021, were enrolled in our study and divided into discovery and validation cohorts at a ratio of 7:3. LASSO regression method was applied for data dimensionality reduction and feature selection. The nomogram for the occurrence risk of colorectal ademomatous polyps was constructed based on multivariate logistic regression. The predictive performance of the model was evaluated regarding its discrimination, calibration, and clinical applicability.Results: A total of 10 high-risk factors were independent predictors of the colorectal ademomatous polyps occurrence and incorporated into the nomogram, including older age, male, hyperlipidemia, smoking, high consumption of red meat, high consumption of salt, high consumption of dietary fiber, Helicobacter pylori infection, non-alcoholic fatty liver disease and chronic diarrhea. The model showed favorable discrimination values, with the area under the curve of the discovery and validation cohorts 0.775 , 0.755-0.794) and 0.776  respectively. The model was also well-calibrated, with Hosmer-Lemeshow test P = 0.370. In addition, the decision curve analysis revealed that the model had a higher net profit compared with either the screen-all scheme or the screen-none scheme.Conclusion: In this prospective study, we established and validated a prediction model that incorporated a list of high-risk features related to colorectal ademomatous polyps occurrence, showing favorable discrimination and calibration values. Colorectal cancer (CRC) has become the fifth most common cause of cancer-related death in China. About 555,477 individuals were diagnosed with CRC, and 286,162 patients died of CRC in 2020 Individuals with colorectal ademomatous polyps are easily diagnosed now by using the wider application of fecal occult blood testing, fecal immunohistochemical test, flexible sigmoidoscopy, colonoscopy, computed tomographic colonography or colon capsule endoscopy, etc. Nomogram has been accepted as a reliable prediction model to quantify the risk of a clinical event by constructing a simple and intuitive graph A total of 3576 confirmed eligible participants, including 2520 colorectal ademomatous polyps and 1056 non-polyp controls, were enrolled in this prospective study from the Department of Gastroenterology in the First Affiliated Hospital of Nanjing Medical University from June 2019 to December 2021. For analysis purposes, we randomly divided all 3576 participants into a discovery cohort  and a validation cohort  , sex . Anthropometric measurements: body mass index (BMI), calculated by height and weight. Family history: the first-class family history of colorectal tumors. Comorbidity history: Helicobacter pylori (H. pylori) infection, non-alcoholic fatty liver disease (NAFLD), gallbladder diseases , diabetes mellitus, hypertension, hyperlipidemia . Laboratory examinations: fasting blood glucose, blood routine examination . Chronic constipation: defecate less than 3 times per week and last for over 6 months, with hard and less stools. Chronic diarrhea: defecate over 3 times per week and last for over 6 months, defecate more than 200 grams a day, with undigested food, pus, blood or mucus. And lifestyle factors: smoking , alcohol use , high consumption of red meat (HCRM) , high consumption of greasy food (HCG) (2 or more times a week), high consumption of salt (HCS) (2 or more times a week), high consumption of pungency (HCP) (2 or more times a week), high consumption of dietary fiber (HCDF) , physical activity . These factors were chosen because of their hypothetical roles in the development of colorectal adenomatous polyps.2 tests or Fisher's exact test appropriately. Continuous variables were described as median ± standard deviation (SD) and compared using Student's t-test. We used SPSS 24.0 and R software version 3.6.1  for statistical analysis. A two-sided P-value of < 0.05 was considered statistically significant.Baseline characteristics of patients with and without colorectal ademomatous polyps in the discovery and validation cohorts were compared. Categorical variables were presented as the number (%) and assessed using the χIn the discovery cohort, to address the impacts of over-fitting, the Least Absolute Shrinkage and Selection Operator (LASSO) regression method was applied using the glmnet package in R project Based on the above results, a prediction model for colorectal ademomatous polyps was constructed using the rms package of R project, providing a visual tool for clinical application. The prediction model was represented by a nomogram based on independent risk factors identified by multivariate analysis. Briefly, the nomogram found the position of each variable on the corresponding axis, and found a point for each variable on the top rule; then all scores were added together and the total was collected. Finally, the corresponding risk probability of the individual colorectal ademomatous polyps was predicted with the lowest rule by adding the scores of all selected variables.To verify the predictive ability of the model, the receiver operating characteristic (ROC) analysis, calibration curve and decision curve analysis (DCA) were used in both the discovery and validation cohorts. Discriminant ability means the ability of the nomogram to distinguish events from non-events by calculating the area under the curve (AUC) and the associated 95% confidence interval (CI). The range of AUC was 0.5-1.0, with 0.5 indicating random prediction and 1.0 perfect prediction. It is accepted that an AUC between 0.5 and 0.7 indicates low prediction accuracy, between 0.7 and 0.9 indicates moderate prediction accuracy, and above 0.9 indicates high prediction accuracy. Subsequently, the consistency between the predicted results and the actual results was evaluated by Hosmer-Lemeshow (H-L) test and calibration curve. The clinical utility of the model was assessed by DCA. The x-axis represented the percentage of threshold probability and the y-axis represented the net benefit of the predictive model. The net benefit was calculated by subtracting the proportion of false positives from the proportion of true positives and weighted by the relative harm of foregoing detection compared with the negative consequences of an unnecessary detection Among the 3576 study participants, 2520 (70%) were colorectal ademomatous polyps. Participants in the colorectal ademomatous polyps group were older, had higher BMI, were more likely to be male, smokers, high consumption of red meat, pungency, greasy food and salt, hyperlipidemia, NAFLD, gallbladder polyps, chronic diarrhea, hypertension and H. pylori infection, while had less proportion of high consumption of dietary fiber. Alcohol user, physical activity, family history of colorectal tumors, gallstones, constipation and blood routine examination were not significantly different between the groups. The validation cohort has similar characteristics to the discovery cohort. Details were shown in Table When the AUC reached its maximum value, the most appropriate tuning parameter λ was 0.007, and the λ corresponding to 1-SE was 0.026 . Additionally, the proposed model was well-calibrated using the H-L test, yielding a non-significant P value of 0.370. As shown in Fig. To validate the performance of the resulting nomogram, we performed internal validation using an independent validation cohort. In Fig. The impact of various modifiable lifestyle patterns and clinical risk factors on colorectal ademomatous polyps has been extensively studied Gender and age are unmodifiable and important predictors for colorectal ademomatous polyps. Pooled studies have reported that the prevalence of colorectal adenomatous polyps increases progressively with age in both men and women and are more common in men than in women in every age group About 50% of the global population is infected with H. pylori, and several researchers have found that H. pylori infection is associated with the occurrence of colorectal polyps An association between NAFLD and colorectal ademomatous polyps was also observed in this study, consistent with previous studies, indicating a moderate association Our study found that chronic diarrhea was an independent risk factor for colorectal ademomatous polyps. However, few studies have been conducted on the association between intestinal dysfunction and colorectal adenomatous polyps, the molecular mechanism remain poorly understood. It may be related to active intestinal peristalsis, which may lead to intestinal epithelial cell proliferation, mucosal inflammation and intestinal flora imbalance Smoking is a significant and well-documented modifiable risk factor for colorectal adenomatous polyps. Studies have consistently shown that the proportion of colorectal adenomas in smokers is significantly higher than that in non-smokers The nomogram we constructed showed better discriminatory ability in the discovery and validation cohorts. Compared with the previously published Western colorectal adenomas detection model, the current model has more risk factors than the previous models, including various dietary factors. Shaukat et al Specific strengths and limitations deserve careful attention when interpreting our results. A major strength of our study is that most of variables included in this model are usually available from the patients' history, which ensures that these factors are readily available in clinical practice. The ROC curve results of our model showed that its sensitivity and specificity were very good, the calibration curves showed that the predicted probability was in good agreement with the actual probability, and the DCA also showed that the model had high clinical practical value. This study still has some limitations, which should be recognized and considered. First, these limit the applicability and generalizability of the nomogram due to the relatively small sample size of the validation cohort in our analysis. Moreover, since the lifestyle data may have subjective elements, the inherent recall bias is more or less unavoidable. Furthermore, some clinical features, such as the use of insulin, C-peptide, NSAIDs, and aspirin, are also important in the evaluation of polyps In conclusion, in this study, we developed and validated a model based on the most readily available clinical features for personalized prediction of colorectal adenomatous polyps. The model showed good calibration and discrimination values and clinical applicability, which is valuable for identifying asymptomatic individuals with coloretcal adenomatous polyps and selecting high-risk target groups for colonoscopy screening. We believe this model will be a good clinical decision-making support tool. However, larger prospective studies and external validations are necessary to confirm our findings and further optimize the model.


Hearing loss etiology depends on the population studied as well as on the ethnicity and the socio-economic condition of the analyzed region. Etiological diagnosis contributes to the improvement of preventive measures and to the early identification of this deficiency.To identify the etiological factors of hearing loss and its prevalence in a tertiary hospital in southern Brazil, to verify the frequency of mutations in GJB2 and GJB6 genes, and to correlate the degree of hearing loss with the etiological factors of deafness.This prevalence study involved 140 children with bilateral sensorineural or mixed hearing loss. Medical history, physical examination, audiometry, and evoked auditory brainstem response were conducted. Imaging and genetic examinations were also performed.GJB2: p.Try172* and p.Arg184Pro. One case with homozygosis of del(GJB6-D13S1830) was found. Regarding severity of hearing loss, in 78.6% of the cases the degree of hearing loss was profound and there were no significant differences when comparing between etiologies.Etiologies and their prevalence were as follows: (a) indeterminate causes, 31.4%; (b) conditions related to neonatal period, 22.1%; (c) genetic, 22.1%; (d) auditory neuropathy, 10%; (e) other factors , 7.9% and (f) congenital infections, 6.4%. Within the genetic cases, ten homozygous and seven heterozygotes of the 35delG mutation were identified, besides two cases of rare variants of The number of indeterminate etiologies is still high and congenital CMV infection may be a possible cause of undiagnosed etiology for hearing loss. The predominance of etiologies related to neonatal conditions and infectious causes are characteristic of developing countries. The most prevalent mutation was 35delG, the main GJB2 gene, probably because of the European influence in the genotype of our population. Deafness is the most common congenital sensory deficiency, with an incidence of one to two cases per 1000 live births.9The main etiological factors of hearing loss have a variable prevalence since they are directly influenced by the socio-economic development, ethnicity, and region of a given country.Diagnostic evaluation of childhood hearing loss includes the investigation of patient history and physical examination, with audiology and electrophysiology testing. By performing additional investigation such as multidisciplinary evaluation, genetic and imaging tests,The most important genetic tests are those that investigate the mutations of the Gap Junction Protein Beta 2 (GJB2) and Gap Junction Protein Beta 6 (GJB6) genes, which encode the 26 and 30 connexins, respectively. GJB2 mutations are the most prevalent, accounting for more than 50% of cases of non-syndromic genetic hearing loss. The 35delG mutation of the GJB2 gene is the most common.The identification of the main etiologies of childhood deafness is important for the primary prevention of this deficiency, through public health measures such as vaccination and improvement of maternal and child health. The early diagnosis of genetic deafness may also contribute to preventive measures, through genetic counseling.The primary objective of this study was to identify the most prevalent etiologies of hearing loss in a tertiary hospital in southern Brazil. Secondary objectives were to verify the prevalence of mutations in the genes of connexins 26 and 30 and to correlate the degree of hearing loss with the etiology of deafness.This was a cross sectional study nested in a retrospective cohort in which patients from an outpatient clinic of a reference center for childhood deafness in tertiary hospital in southern Brazil were included. Referrals to this clinic occurred for two reasons: (a) failure in neonatal hearing screening (NHS) or (b) investigation and treatment of already diagnosed hearing loss.Inclusion criteria for this study were as follows: (a) age up to 12 years incomplete; (b) bilateral sensorineural or mixed hearing loss; and (c) hearing loss that is congenital or acquired in the neonatal period. The project was approved by the Research Ethics Committee of the hospital where the research was conducted (number 150464). All adults responsible for the children signed the informed consent form.At the first appointment of each patient, a medical history was gathered to elicit important information in order to characterize the child’s profile, the presence of risk factors for deafness and to hypothesize the etiological diagnosis of hearing loss. The assessed risk factors for hearing loss in childhood were the ones defined by the Joint Committee on Infant Hearing.Hearing loss acquired before birth, regardless of the time of manifestation of symptoms was considered congenital in this study. The term “conditions related to neonatal period” was used to describe neonatal conditions or complications that cause hearing loss and occur shortly after birth and may extend beyond the first month of life of the newborn. These conditions/complications are part of the risk factors determined by the Joint Committee on Infant Hearing, 2007.In order to demonstrate that the hearing loss was congenital or acquired in the neonatal period, the first criterion was the etiology of deafness. In case of undetermined etiology, we considered the result of the NHS. So, we assumed that patients with hearing loss without a defined etiology that had failed in the NHS were congenital.The type of hearing loss was defined by specific frequency auditory evoked potential and/or visual reinforcement audiometry . The assessment of the degree of hearing loss was performed using the Interacoustics Eclipse EP25 ABR system® (Denmark) with NB-chirps® at 500 Hz, 1000 Hz, 2000 Hz and 4000 Hz or the Interacoustics AD 27 audiometer  and was classified according to the World Health OrganizationLaboratory tests to investigate congenital infections were carried out in the prenatal care of the pregnant women. In cases where the mother had not performed prenatal care, investigation was performed at the time of delivery and, depending on the result, also in the newborn, by means of serological tests, as recommended by the Brazilian Ministry of Health.Serology for cytomegalovirus (CMV) has also not been investigated, due to the low sensitivity and specificity of the presence of immunoglobulin M (IgM) in the diagnosis of congenital infection by this virus. Viral isolation in a culture of human fibroblasts or detection of viral DNA by polymerase chain reaction (PCR) in baby’s urine or saliva samples. This test was performed in symptomatic infants only.Patients with suspected inner ear malformation  or candidates for cochlear implants with severe or profound hearing loss underwent imaging examination: computed tomography (CT) and/or magnetic resonance imaging (MRI) of the ears. Patients with suspected syndromes, neurological or ophthalmologic disorders were referred for specialized evaluation.Blood samples were collected from all non-syndromic children for DNA extraction and analysis of GJB2 gene mutations and deletion del(GJB6-D13S1830) of the GJB6 gene. Five mL of blood were collected in a tube with ethylenediaminetetraacetic acid (EDTA) and the material sent to the medical genetics laboratory to extract deoxyribonucleic acid (DNA) with the GENTRA Puregene Kit .For the genetic analysis of connexin 30, the samples were subjected to PCR for isolation of the fragment of interest, using three primers (1 forward and 2 reverse).1)Conditions Related to Neonatal Period (CRNP): Neonatal Intensive Care Unit (ICU) stay >5 days or extracorporeal ventilation, assisted ventilation, use of ototoxic drugs (gentamicin and tobramycin) or loop diuretics (furosemide) and hyperbilirubinemia requiring transfusion.2)Congenital or neonatal infection (CNI): infections acquired in the pre and perinatal period such as syphilis, toxoplasmosis, rubella, CMV, herpes virus, and acquired immunodeficiency virus (HIV).3)Genetics: syndromic hearing loss (SHL) and non-syndromic hearing loss (NSHL). SHL consists of HL that presents with anomalies of the eye, kidney, the musculoskeletal and the nervous systems, as well as pigmentary disorders or others whereas, in our study, NSHL refers to patients with a genetic mutation in the GJB2 and/or GJB6 gene proven by molecular examination.4)Auditory neuropathy spectrum disorder (ANSD): defined as the presence of otoacoustic emissions and/or cochlear microphonism and the absence of significant responses or changes in ABR.235)Undetermined: after excluding other causes of hearing loss;6)Others: malformations of the external, middle, or internal ear and central etiologies.In order to facilitate the comparison of the data found with those of other studies, we grouped the etiological factors into six main groups:Another type of classification we performed was according to the steps of the investigative process of the etiology behind a hearing loss. The reason for that was to find how many patients can be diagnosed in one or two steps and how many needs more complex procedures.1)Medical history and physical examination: can identify conditions related to the neonatal period and congenital or neonatal infections, as well as most syndromes.2)Auditory exams: can detect ANSD by means of suggestive findings in otoacoustic emissions and BERA.3)Imaging exams: can detect the presence of inner ear malformations4)Genetic tests: identifies the presence of mutations in the investigated genes that confirms if the hearing loss has non-syndromic genetic origin5)Expert assessment: when patients with a set of suggestive changes of syndromes are referred for evaluation in the medical genetics service for the etiological diagnosis.The groups and criteria used to define each were as follows:A descriptive statistical analysis was performed. Quantitative variables were described by mean ± standard deviation and categorical variables, by total and absolute frequency. Pearson’s Chi-square test was used to compare the categorical variables. The SPSS 18.0 software was used for statistical analysis .In the period from January 2015 to December 2017, 258 children were referred to the outpatient clinic: 103 patients (39.9%) due to having failed the NHS and 155 patients (60.1%) for investigation and treatment of already diagnosed hearing loss. Deafness was confirmed in 239  patients, being bilateral in 213 . Among these, 140  patients met the inclusion criteria, as shown by the organogram in After the initial analysis, 140 children with a mean age (± standard deviation) at the first visit of 2.00-years  were evaluated. Seventy-two patients (51.4%) were male. As for race/color, 89.3% identified themselves as white, 7.9% black, 2.1% mixed, and 0.7% indigenous. Sixty-eight children (50.7%) were the children of multiparous mothers and 98.5% of the mothers performed prenatal consultations. Regarding the degree of hearing loss in the best ear, the mean was 96.43 dB (± 25.05).Among evaluated children, 85 (60.7%) had at least one risk factor for childhood hearing loss.The most prevalent etiological groups were the ones of conditions related to neonatal period (Group 1) and genetics (Group 3), with 31 cases (22.1%) each. In 44 patients (31.4%) it was not possible to determine the cause of the hearing deficit (Group 5), as shown in In Group 1 , neonatal ICU stay for more than five days was the most prevalent factor associated with hearing loss, occurring in 48 patients (34.3%), followed by mechanical ventilation (20.7%), ototoxic use (19.3%), and exchange transfusion for neonatal jaundice (6.4%).CMV was the most prevalent infection of Group 2, with four cases (2.9%). We also identified two cases (1.4%) of congenital syphilis, 2 (1.4%) of toxoplasmosis and 1 (0.7%) with herpes virus infection. All these children were diagnosed with the congenital infection before the first consultation at the outpatient clinic. Seven children were symptomatic: four with CMV infection, two with toxoplasmosis and one with the herpes virus.Hearing loss of genetic origin was divided into syndromic, 41.93%, and non-syndromic, 58.06%. Among the syndromic ones, we found two cases of CHARGE, one of Goldenhar, one of Waardenburg, one of Treacher Collins, one Stickler and seven cases of syndromic hearing loss, still without a definite diagnosis.The genotypes of the 18 patients with non-syndromic genetic hearing loss and the number of cases of each are shown in Although genetic tests were performed on all non-syndromic children, regardless of any other possible etiology for hearing loss, only those with no other hypothesized etiology presented altered genetic tests. An important finding was that the final etiology in 44.44% of the children with a positive family history of hearing loss was genetic. Of those, 29.6% were non-syndromic (six homozygotes and two heterozygotes for the 35delG mutation) and 14.8% were syndromic .Imaging exams (CT and/or MRI of the ears) were performed in 131 children (93.6%). Eight of these (6.1%) had inner ear malformations. Among them, we found a case of a single vestibulocochlear cavity, one of incomplete partition type 1, three of incomplete partition type 2, one of the vestibular enlarged aqueducts and two of cochlear nerve agenesis. Among the external and middle ear malformations: three cases of microtia and bilateral external auditory canal agenesis, one of them associated with middle ear malformation. All external ear malformations were found in syndromic patients , that is, they were not considered as the main etiologies. Also, from cases classified as central nervous system etiology, one was due to cortical malformation and two as sequelae of intracranial hemorrhage.Considering all the children with an established etiology for the hearing loss, 49 (51%) had the etiology established at the first appointment through medical history and physical examination. Genetic tests defined the cause in 18.8% of the cases. In According to this study, the two most prevalent etiologies for hearing loss were CRNP and CNI, which were responsible for a greater number of cases when compared with genetic etiology. Among NSHL groups, the 35delG mutation of the GJB2 gene was responsible for most cases.It is difficult to compare our results with the ones from other studies. The differences in methods between ours and other studies are mainly in inclusion criteria  and in classifications . However, because this is a prevalence study, results are expected to vary according to the genetic and socioeconomic characteristics of the analyzed populations and, since there are not similar studies conducted within the studied population, comparisons become less relevant. The results are therefore of great importance for the study of etiologies in different world scenarios.The predominance of etiologies related to neonatal conditions and infectious causes are characteristic of developing countries, where investments on promotion and prevention of hearing health are limited.27Conditions related to the neonatal period (CRNP) were responsible for hearing loss of 22.1% of the 140 patients evaluated in a study by Walch et al. 19.8% of hearing loss was due to neonatal conditionsThe prevalence of congenital infections was 6.4%, possibly reflecting improvements in hygiene methods, in prenatal and newborn care, as well as of vaccination campaigns. Rubella, which was once the most common viral cause of hearing loss,In contrast to other congenital infections, CMV is being more studied in recent years, since it has become first place among the viral causes of deafness.,33With increasing control of neonatal conditions and infectious diseases plus the improved knowledge of deafness-related genes, genetic causes have become the main etiology of hearing loss in developed countries, making up to 50%–60% of cases. According to literature from across the globe, the prevalence varies from 15% to 60%.25NSHL was responsible for hearing loss in 12.9% of the children studied. Costa et al. also evaluated the causes of hearing loss in Brazilian children, and 16% of the cases were confirmed as genetic by molecular tests.Most of the mutations found in this study were in the GJB2 gene, which encodes connexin 26 . The most prevalent mutation was 35delG, the main gene GJB2, ten mutations were found: three 35delG with biallelic expression (homozygous) and seven monoallelic (heterozygous).Hearing loss occuring in homozygous patients and heterozygotes are called carriersTwo other pathogenic variants of GJB2 were also found in heterozygous patients for 35delG. They were c.551G>C (p.Arg184Pro) and c.516G>A (p.Try172*). In this study, the p.Arg184Pro mutation was found in heterozygosis associated with the 35delG variant. This association has also been described in other studies.36The variant c.516G>A (p.Try172*) was described in the Brazilian population by Oliveira et al., through two cases of profound hearing loss with the p.Try172* in heterozygosis, one of them associated with 35delG.The deletion del(GJB6-D13S1830), the most frequent of GJB6 mutations according to the literature, was found in a child in this study. These deletions remove all or part of the GJB6 gene, or regions neighboring it, and cause deafness when present in homozygosis or in heterozygosis in combination with a recessive mutation in the GJB2 gene. Although in most cases, they occur in combination with other GJB2 mutations, in this study, the patient was homozygous.Since the presence of risk factors would not exclude the possibility of concomitant genetic alteration, it was decided to perform the genetic tests in all non-syndromic children, independently of any other etiology being more likely. However, only those without a possible etiology presented alterations in the genetic tests. This result raises the argument about the need to perform genetic tests in all non-syndromic children.Syndromic hearing loss was found in 9.3% of the total children in the study. Considering only the genetic etiology group, 41.93% were syndromic. According to the literature, prevalence is usually around 30%.The prevalence of children who remained without an etiological diagnosis was 31.4%. However, with the GJB2 and GJB6 mutations, 40% of nonsyndromic genetic hearing loss can be identified.43Congenital CMV infection is another possible cause of undiagnosed etiology for hearing loss. The explanation is probably related to the high prevalence of this infection and the difficulty of diagnosing the newborn because most are asymptomatic at birth and there is a short window of time to analyze CMV viral load in urine and/or saliva.About the steps of the investigative process of the etiology behind a hearing loss, it was already expected that the majority of cases could be identified through medical history and physical examination, since it was known that there is a high prevalence of hearing loss related to neonatal conditions. We observed that genetic tests were the second largest factor responsible for the definition of etiology (18.8%), which confirms the importance of the investigation of mutations in connexins 26 and 30 in cases of congenital hearing loss.No impact of the different etiologies on the degree of hearing loss has been identified, which is in conformity with available literature data.The predominance of conditions related to neonatal period and infectious causes are characteristic of developing countries, and the high number of CRNP may also be due to our hospital being a reference center for high-risk pregnancy. The low prevalence of congenital infections possibly reflects improvements in hygiene methods, prenatal and newborn care, as well as of vaccination campaigns, but we believe that congenital CMV may play a bigger role than is currently known. The most prevalent mutation was 35delG, the main gene GJB2, probably because of the European influence in the genotype of our population. Fifty-one percent of the children with deafness had the etiology established at the first appointment, through medical history and physical examination. Genetic tests defined the cause in 18.8% of the cases.The authors declare no conflicts of interest.