Atresia Of External Auditory Canal Research Articles

External auditory canal atresia affecting the horizontal canal of a 2‐year‐old Labrador Retriever dog

AbstractA 2‐year‐old, female neutered, Labrador Retriever dog was presented with left otalgia. Otoscopic examination revealed a blind ending left external ear canal. Magnetic resonance imaging confirmed an abrupt narrowing of the lateral aspect of the horizontal canal, medial to which the remaining horizontal ear canal and middle ear cavities contained well‐delineated, homogenous, T2w, fluid‐attenuated inversion recovery and T1w hyperintense, non‐contrast enhancing material. A diagnosis of external auditory canal atresia was made based on the imaging findings. Considering the patient's age and absence of preceding trauma, a congenital cause was considered most likely. Surgical treatment by way of a total ear canal ablation with lateral bulla osteotomy was performed. At the re‐check appointment, the surgical site had healed well and there were no associated complications noted; a telephone call with the owner 5 months later documented no clinical concerns.

Demographic, Functional, and Risk Factors Characterization in Ecuadorian Mestizo Patients With Microtia: A Retrospective Study.

This paper compares demographic, morphological, functional, and risk factors between isolated and familial forms of microtia in Ecuadorian mestizo patients. The authors did an epidemiological, and retrospective study with 112 patients divided into isolated microtia (n = 91) and familial microtia (n = 21). Patients with syndromic microtia were not included. In isolated microtia, the mean age was 11.80 ± 16.9, and the most prevalent age group was from 5 to 9 years, with 45.0%; males were 58.2%, and 91.2% of patients were born in a city above 2500 meters about sea level. In familial microtia, the mean age was 15.57 ± 17.2. There were no statistically significant differences between the analyzed variables. In isolated microtia, 41.8% of patients had bilateral involvement, 40.7% had grade 1 microtia in the right ear (RE), and grade 1 in the left ear was 47.3%; external auditory canal atresia of RE was present in 62.6%, and in left ear in 31.6%. External auditory canal atresia sidedness was mostly unilateral in both groups. Most patients did not have tags or pits (78% and 81% in RE and 85.7% and 71.4%). Most patients had moderate hearing loss in both ears. The authors found an association between both microtia forms with external auditory canal atresia in RE; only 20% of patients had unilateral auricular tags or pits in both groups. The authors also found a high incidence (18.75%) of familial microtia, which suggests a distinct pathological genetic component than the more prevalent isolated cases. The authors found a high association of microtia cases from the Ecuadorian highlands above 2500 meters about sea level (over 90%). The presence of "social" intake of alcohol during pregnancy showed over twice the chance of having a child born with microtia.

Analysis of predictive factors related to long-term hearing and temporal bone development in congenital microtia

ObjectiveTo investigate the predictive factors of long-term hearing threshold and temporal bone development in children with congenital microtia (CM). Methods74 patients (92 ears) with CM enrolled, which all had auditory brainstem response (ABR) results during infancy or toddlerhood, pure tone audiometry (PTA) and high-resolution computed tomography (HRCT) results during childhood or adolescence, and had not undergone any surgery. We compared the relationship between ABR, auditory steady-state response (ASSR), the affected side, auricular morphology, presence of external auditory canal stenosis or atresia, PTA average, mastoid pneumatization, Jarhsdoerfer scores, and wether cholesteatoma exists. ResultsThe average age of ABR in 92 ears was 2.72 ± 3.52 years old, PTA was 7.26 ± 2.51 and HRCT was 6.91 ± 2.76 years old. ABR-AC was related to PTA average, mastoid pneumatization, Jarhsdoerfer scores, and wether cholesteatoma exists in CM. While ABR-ABG was related to all of these factors except Jarhsdoerfer score, and ABR-BC had no relationship with any of them. ASSR only showed correlation with frequencies of 1, 2kHz and was related to Jarhsdoerfer score, with no other correlations observed. The impaired ear side showed no relevance. However, auricular morphology was related to all of these factors except wether cholesteatoma exist. External auditory canal stenosis or atresia was related to PTA average, but unrelated to mastoid pneumatization. ConclusionThe ABR examination in the infant stage plays a crucial role in predicting the long-term hearing and temporal bone development in patients with CM.

Treatment of external auditory canal stenosis and atresia after transcanal endoscopic ear surgery

PurposeTo discuss the treatment of external auditory canal stenosis or atresia occurring as a complication of transcanal endoscopic ear surgery. Materials and methodsWe retrospectively analyzed the medical records of 11 patients who developed external auditory canal stenosis or atresia after undergoing transcanal endoscopic ear surgery. The 10 patients with stenosis were treated with external auditory canal expansion via drainage tube insertion; 2 of these patients further received local injections of triamcinolone acetonide. One patient with atresia was treated with meatoplasty surgery followed by tube insertion and triamcinolone acetonide injection. ResultsThe stenosis/atresia improved in all patients, and the external auditory canal was unobstructed without restenosis. ConclusionsStenosis/atresia of the external auditory canal after transcanal endoscopic ear surgery should be treated with dilation therapy/meatoplasty in a timely manner to prevent progressive hyperplasia of the scar and regain a normal-sized ear canal.

EPH147 The Costs of Unaddressed Hearing Loss in Chilean Children with Bilateral Microtia and External Auditory Canal Atresia and Cost Effectiveness of Different Treatment Interventions

EPH147 The Costs of Unaddressed Hearing Loss in Chilean Children with Bilateral Microtia and External Auditory Canal Atresia and Cost Effectiveness of Different Treatment Interventions

The role of MRI in the prenatal diagnosis and classification of fetal microtia

ObjectiveTo investigate the role of MRI in the diagnosis and classification of fetal microtia.MethodsNinety-five fetuses with suspected microtia based on ultrasound and MRI performed within 1 week were enrolled in this study. The diagnosis based on MRI was compared with postnatal diagnosis. Among the microtia cases suspected on the basis of MRI, mild and severe cases were further classified. In addition, external auditory canal (EAC) atresia was evaluated by MRI in 29 fetuses with a gestational age > 28 weeks, and the accuracy of MRI in the diagnosis and classification of microtia was determined.ResultsOf 95 fetuses, 83 were considered to have microtia on the basis of MRI, 81 were confirmed to have microtia, and 14 were found to be normal according to postnatal diagnosis. Among 190 external ears in 95 fetuses, 40 ears were suspected to have mild microtia, and 52 ears were suspected to have severe microtia on the basis of MRI. According to the postnatal diagnosis, mild and severe microtia were confirmed in 43 and 49 ears, respectively. Among the 29 fetuses with a gestational age > 28 weeks, 23 ears were suspected to have EAC atresia according to MRI and 21 ears were ultimately confirmed to have EAC atresia. The accuracy of MRI in diagnosing microtia and EAC atresia was 93.68% and 93.10%, respectively.ConclusionMRI shows good performance in diagnosing fetal microtia and has the potential to evaluate its severity on the basis of classification and EAC status.Clinical relevance statementThis study was aimed at investigating the role of MRI in the diagnosis and classification of fetal microtia. MRI shows good performance and can help evaluate microtia severity and EAC atresia, thus allowing for better clinical management.Key Points• MRI is a useful adjunct to prenatal ultrasound.• MRI has a higher accuracy rate than ultrasound in diagnosing fetal microtia.• The accurate classification of fetal microtia and the diagnosis of external auditory canal atresia through MRI may help guide clinical management.

Unilateral Traumatic Atresia of External Auditory Canal: A Case Report

External Auditory Canal (EAC) atresia, which can be acquired or congenital, is a condition in which the EAC is not present. A blind sac in the external acoustic meatus is the result of intraluminal or extraluminal processes of various aetiologies, which can lead to acquired atresia of the EAC. Acquired EAC atresia is a rare disorder of the EAC, and it is extremely uncommon for it to be brought on by direct trauma. In present investigation, a 31-year-old female patient, leading to onset of right temporal discomfort and impaired hearing in the right ear. On examination, a 10×1 cm tender scar was present extending from right parietal region till right zygomatic arch with stenosis in the right external auditory meatus. Facial nerve examination revealed loss of wrinkling on right side with slight deviation of the angle of mouth to left side. High Resolution Computed Tomography (HRCT) temporal bone showed soft tissue causing complete occlusion of right EAC. Patient underwent right EAC atresiaplasty with canaloplasty and canal reconstruction. Facial nerve weakness persisted postoperatively. Patient is still on follow-up and has improved symptomatically with no restenosis. Surgical management of EAC atresia is very challenging, thus it needs meticulous planning and long term follow-up for good results which was evident in the present case.

Atresia or severe stenosis of the external auditory canals with normal auricles in children

In the article we present the experience of observing 27 children with bilateral stenosis or atresia of the external auditory canals with normal or slightly hypoplastic auricles. Three children had bilateral stenosis of the external auditory canals due to abnormal or premature fusion of the skull bones. The remaining 24 children had external auditory canals atresia in the bone part or throughout. 9 of them had a syndrome of deletion of the long arm of chromosome 18, 1 child had a mosaic form of Edwards syndrome. The average age at the time of diagnosis was 4 years 3 months. Atresia of external auditory canals in normal auricle is often caused by abnormalities of 18 pairs of chromosomes, and severe stenosis of external auditory canals can be observed in children with craniostenosis and other anomalies of the skull bones.

Acquired Atresia of External Auditory Canal Associated With Synovial Chondromatosis of the Temporomandibular Joint

Synovial chondromatosis (SC) is a rare disease involving long bones, rarely affecting the temporomandibular joint (TMJ). It can manifest as preauricular swelling, pain, and joint dysfunction. This report represents the case of acquired atresia of external auditory canal in association with SC of TMJ. Active evaluation and treatment of TMJ pathology seem essential when addressing the acquired atresia of external auditory canal.

Salivary Gland Choristoma in External Auditory Canal: A Case Report

Introduction Salivary gland choristomas have been described in the middle ear but tend not to involve the external auditory canal. Case presentation A 6-year-old boy with situs inversus totalis presented with congenital hearing loss in the left ear due to external auditory canal atresia. High resolution computed tomography of the temporal bone demonstrated a soft tissue obstruction of the external auditory canal with a normal middle ear. Histopathologically, this was a salivary gland choristoma. Post operatively the patient had a facial nerve palsy. Conclusion Salivary gland choristomas of middle ear have been reported, but have not been described with external auditory canal atresia and situs inversus totalis.

Isolation, culture, and identification of ceruminous gland cells.

External auditory canal (EAC) stenosis or atresia usually requires a skin graft to repair, but due to the lack of a graft containing functional glands, postoperative complications such as infection and eczema are common. The aim of this study was to isolate and characterize seed cells for the construction of tissue engineered EAC skin containing ceruminous gland by isolating and cultivating cells of ceruminous gland. In this study, EAC skin samples were harvested from adult goats for ceruminous gland cell isolation. Cell morphology and proliferation rates, expression of CK7, CK8, CK18, and CK19 (glandular cell specific-markers), and secretion of β-defensin-1, lysozyme, and polysaccharides were evaluated at different passages to verify the presence of ceruminous gland cells and determine whether function and proliferation potential were maintained. Ceruminous glands were successfully isolated and extracted from goat EAC skin. Furthermore, the isolated glandular cells maintained robust proliferation potential, exhibited high expression of CK7, CK8, CK18, and CK19, and vigorously secreted β-defensin-1, lysozyme, and polysaccharides in this culture system. However, expression of glandular cell specific-markers and secretory function gradually declined with increasing passage number, indicating dedifferentiation of the subcultured ceruminous gland cells after five passages. In conclusion, ceruminous glands were successfully isolated, cultured, and expanded from goat EAC skin using the serumcontaining culture system. Importantly, the isolated glandular cells retained robust proliferation potential and maintained their phenotype and function in early passages (P1-P3), indicating the method's potential application for ceruminous gland regeneration.

Congenital atresia of external auditory canal with choristoma: A rare case report

Congenital aural atresia (CAA) is the abnormality of the auricle and/or external auditory canal where there is closure of the external auditory canal which may be associated with microtia and anomalies in the middle ear, inner ear, or temporal bone. It can be solid or membranous type of atresia. To identify the type of defect, high-resolution computed tomography (HRCT) temporal bone is useful. After identifying the defect, the patient can be planned for canaloplasty or atresiaplasty with split skin graft. A 6-year-old boy was brought to the otorhinolaryngology outpatient department with complaints of deformity of the left ear since birth. HRCT temporal bone showed isolated left external auditory canal atresia. Echocardiogram showed dextrocardia with situs solitus and USG abdomen revealed situs inversus of the abdominal organs with no significant abnormality. After proper evaluation of the child, after obtaining preanesthetic fitness, the child had undergone atresiaplasty with split skin graft under general anesthesia. Soft tissue that was excised from the external auditory canal was sent for histopathological examination, which revealed the presence of salivary gland tissue with lymph nodes showing reactive changes. These features were suggestive of possibility of choristoma of the left external auditory canal. CAA occurs in the defect during embryological development which may result in deformity of the auricle and external auditory canal. The surgical management of congenital external auditory canal atresia is atresiaplasty, and hearing rehabilitation (bone anchored hearing aid) should be given in case of no improvement in hearing. The surgery will be challenging because of altered anatomy of surgical landmarks. Choristoma is a tumor-like growth of normal tissue in an abnormal place. It is a benign condition, which may be found commonly in the head-and-neck region such as presence of salivary gland tissue in the middle ear, presence of gastric mucosa in the tongue and presence of osseous or cartilaginous masses in the intraoral soft tissues. Total excision can be done for small and pedunculated tumors, and care should be taken not to injure facial nerve. CAA may not necessarily present with deformities in the external ear (pinna), but Congenital aural atresia cases may not always present with deformities of the pinna,but it is crucial not to miss such cases. These patients may be evaluated by doing High Resolution Computed Tomography temporal bone and audiometric assessment such as. Pediatric evaluation is equally important to rule out for any syndromic association. Atresiaplasty or canaloplasty has shown great result for correcting the cosmetic defect. Hearing can be facilitated further using bone anchored hearing aids or cochlear implantation.

Generalized eruptive keratoacanthomas involving the auricles and external auditory canal: A case report and literature review

Objective: The aim of this study was to report a case of Generalized Eruptive Keratoacanthomas (GEKA) involving the auricles and external auditory canal and to review the relevant literature. Methods: A patient with bilateral auricles stenosis and External Auditory Canal (EAC) atresia associated with GEKA is described. We performed a systematic review of the literature to identify and compare similar cases. Results: This case report described a 54-year-old female patient with external auditory canal stenosis and auriclelesion associated with GEKA. A Computed Tomography scan (CT) of the temporal bone. Conclusion: Bilateral auricles stenosis and atresia of EAC associated with GEKA is a rare case. It provides a new perspective for the etiological diagnosis of acquired auricles lesion as well as stenosis and atresia of EAC in the future. The surgical strategy is necessary for the management of the acquired stenosis and atresia of the EAC that associated with GEKA. Further research is needed to increase the number of clinical cases to establish whether and when the surgery is necessary for this disease. Keywords: keratoacanthoma; auricles lesion; ear canal; stenosis; atresia.

Oculo-auriculo-vertebral Spectrum (Goldenhar Syndrome): Presentation of Three Cases

BackgroundThe oculo-auriculo-vertebral spectrum (OAVS) includes three closely related rare congenital diseases of different severity with an incidence of 1/3500-7000 individuals. The involvement is usually unilateral; however, bilateral involvement may also occur. In addition to craniofacial anomalies, defects in the cardiovascular, genitourinary, vertebral, and central nervous systems can be observed as well. The phenotype of the cases is highly variable. Goldenhar syndrome is the most severe form of this condition.Case reportIn total, three instructive cases of Goldenhar syndrome with different features have been reported in the present case study. The most common ear anomalies among these three cases included external auditory canal atresia, helix deformities, preauricular skin tag and/or ear pitting, microtia, and conductive hearing loss. The second case was presented with hemifacial microsomia on the more severely affected right side, and the third case had bilateral Brushfield spots and a dermolipoma ophthalmological findings.ConclusionBased on the findings of the present study, OAVS should also be considered in the differential diagnosis of the cases with facial and ear anomalies.

Hearing rehabilitation with osseointegrated hearing implant in bilateral congenital external auditory canal atresia

Introduction and objectivesCongenital atresia of the external auditory canal (EAC) is a congenital defect present in one in every 10,000–20,000 births. It causes conductive hearing loss, with an air-bone gap of 50–60dB. Early amplification is essential in bilateral cases to ensure normal language development. The aim of this study is to present the osseointegrated hearing implant as a treatment for bilateral EAC atresia, reviewing the audiometric results and the rate of complications. Material and methodsRetrospective analysis of patients diagnosed with bilateral congenital EAC atresia under follow-up in the pediatric ENT clinic of the ENT and Head and Neck Surgery department of a Portuguese Tertiary Hospital, between 2003 and 2019. We reviewed the medical records and collected information on the assessment of the initial audiometric status. In the cases submitted for implantation with an osseointegrated hearing implant, we analyzed the details of follow-up, including immediate and long-term post-operative complications, as well as the audiometric results. ResultsWe present 8 pediatric patients, 6 girls and 2 boys, with a diagnosis of bilateral congenital EAC atresia. The audiometric assessment revealed moderate to severe bilateral conductive hearing loss with a mean speech recognition threshold (SRT) of 51dB. Six patients underwent osseointegrated hearing implantation. All 6 patients showed good audiometric results, with an average SRT of 20dB and closure of the air-bone gap. ConclusionsThe osseointegrated hearing implant was an effective treatment option in these patients, without significant morbidity or complications. Osseointegrated hearing implantation should be considered first line treatment for children with bilateral congenital EAC atresia, as it presents good functional results and a high level of patient satisfaction.

External Auditory Canal Atresia with Otitis Media in a Dog

Ah Reum Kim, Changhee Han, Gunha Hwang, Rakhoon Kim, Woohyun Go, Ji Yeong Lee, Jongbong Lee, Soyon An, Tae Sung Hwang, Dongbin Lee, Jae-Hoon Lee, Hee Chun Lee. J Vet Clin 2021;38:159-62. https://doi.org/10.17555/jvc.2021.38.3.159

Whole-Genome Sequencing Identifies Two Novel Rare Mutations in BMP5 and BMP2 in Monozygotic Twins With Microtia.

Microtia is a rare congenital anomaly of the ear; it is regulated by both genetic and environmental factors. However, the mechanisms underlying its pathogenesis are unknown. In this study, the genomes of 2-year-old twin sisters with right microtia were sequenced using human genome-wide sequencing, an approach useful for identifying mutations in genes responsible for congenital microtia. The phenotypes of the twin sisters included congenital microtia on the right side, abnormal auricle shape in the right external ear, a peanut shape for the residual ear, and complete atresia of the right external auditory canal. In the twin sisters, we identified a previously unknown mutation in BMP5(exon4:c.833- 4C>G), as well as a new mutation (exon2:c.G332T:p.S111I) in BMP2, both of which were confirmed using polymerase chain reaction-based amplification of the corresponding genome regions, followed by first-generation sequencing. The exon4:c.833-4C>G mutation in human BMP5 may be the main cause of microtia in the twin sisters. A pathogenic mutation in human BMP2 (exon2:c.G332T:p.S111I) may be responsible for the facial deformity in the twin sisters. Thus, our study demonstrates the potential of genome-wide sequencing for identifying novel mutations associated with microtia on the whole-genome scale and extends the mutation spectrum of BMP5. Additionally, our data suggest that BMP2 is another pathogenic gene associated with microtia.

Evaluation of the effects auricular reconstruction with Medpor combined with hearing rehabilitation

Objective: To investigate the clinical effects of single-stage auricular reconstruction and hearing rehabilitation in children with microtia and external auditory canal atresia. Methods: Sixty eight cases of microtia with external auditory canal atresia (53 males and 15 females, age from 7 to 12 years, with a median age of 8.8 years), who received operations in Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine from July 2017 to December 2019 were collected.A total of 28 cases received auricle reconstruction with high-density polyethylene (Medpor) framework and hearing reconstructions, among which 20 patients received the traditional external auditory canal and middle ear repair (EACR), and eight patients were implanted bone conduction device bone bridge(BB) simultaneously.In the control group, 40 patients only received Medpor frame implantation for auricle plasty. Postoperative changes in auricle morphology and auditory function and postoperative complications were evaluated. Results: After three to thirty months follow-ups, the auricles shape recovered well in all three groups. The average scores of 14 fine structures in the auricles were 9.43(EACR) and 10.67(BB) points. The average score of auricle symmetry were 6.83(EACR) and 6.00(BB) points. There was no significant difference compared to the auricle reconstruction group (8.23/6.20 points). P>0.05. After surgery, the average hearing improvement in the BB group was 43.33 dB HL and the average speech recognition threshold declined 42.28 dB HL. In the EACR group, the average hearing improvement was 4.13 dB HL and the average speech recognition threshold declined 11.36 dB HL. No vertigo, tinnitus, cerebrospinal fluid leakage and other complications occurred in all the patients. In the EACR group, sensorial hearing loss, auricle stent fracture, ear canal restenosis and ear canal atresia occurred in one patient respectively. In the auricle group, one auricle stent exposure and one facial branch nerve injury occurred. Nearly ten patients had difficulty in hair growth at scalp incisions. Conclusions: The operation of single-stage auricular reconstruction and hearing rehabilitation for microtia is feasible. The methods of hearing reconstruction should be determined by evaluating the development of the inner and middle ear of the patients. For those with poor mastoid development, bone bridge implantation is recommended to achieve a stable and significant hearing effect.

Auricular reconstruction using Medpor combined with different hearing rehabilitation approaches for microtia

Background Congenital microtia-atresia affects patients in two specific ways: severe conductive hearing loss and difficulty in integrating into social environments due to auricle malformation. Aims/objectives To investigate the safety and efficacy of single-stage auricular reconstruction and hearing rehabilitation in children with microtia and external auditory canal atresia. Material and methods From January 2016 to December 2019, we included 32 patients with microtia and external canal atresia who received auricle reconstruction with high-density polyethylene (Medpor) framework and three different hearing rehabilitation approaches at the Ninth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine. Twenty patients underwent the traditional external auditory canal and middle ear repair (EACR), eight patients were implanted with Bonebridge (BB) devices, and four patients were implanted with bone-anchored hearing aid (BAHA) in one stage. Postoperative changes in auricle morphology and hearing and speech recognition and occurrence of complications were evaluated. Results After 6–24 months of follow-up, the auricle shape recovered well in all three groups, and the average score of 14 fine structures in the auricle was 9.43 (EACR), 10.67 (BB), and 9.75 (BAHA) points. The average score of auricle symmetry was 6.83 (EACR), 6.00 (BB), and 6.44 (BAHA) points. No significant differences in auricle shape were observed among the three groups (p > .05). After surgery, the average hearing improvement in the BB group was 43.33 dB, and the average speech recognition threshold declined to 42.28 dB. In the BAHA group, the average hearing improvement was 35 dB, and the average speech recognition threshold declined to 33.5 dB, similar to that of the BB group. However, in the EACR group, the average hearing improvement was only 4.13 dB, and the average speech recognition threshold declined to 11.36 dB. No vertigo, tinnitus, cerebrospinal fluid leakage, facial nerve paralysis, osseointegration failure, and other complications occurred in all the patients. In the EACR group, auricle stent fracture, ear canal restenosis, and canal atresia occurred in one patient each. In the BAHA group, two patients developed local ear infections. Conclusions and significance The procedure of single-stage auricular reconstruction and hearing rehabilitation for microtia is feasible and effective. The appropriate method of hearing reconstruction should be determined by evaluating the development of the inner and middle ear of the patients. For those patients with poor development of the mastoid and ossicular chain, hearing aid devices are recommended to achieve a stable and significant hearing effect.

Changes in the Transcriptome and Proteome of Cartilage in Microtia.

Congenital microtia is a severe physiological defect and is among the most common craniofacial defects. It is characterized by severe auricle dysplasia, external auditory canal atresia or stenosis, and middle ear malformation, though inner ear development is mostly normal with some hearing occurring through bone conduction. Auricular reconstruction is the only treatment for congenital microtia. In this study, the authors integrated messenger ribonucleic acid and mass spectrometry data of cartilage obtained from the affected and unaffected sides of 16 unilateral microtia patients who had undergone ear reconstruction surgery. The authors next performed functional analyses to investigate differences in the proteome of the affected and unaffected ears to elicit molecular pathways involved in microtia pathogenesis. The authors collected 16 pairs samples. Proteomic and transcriptomic analyses identified 47 genes that were differentially expressed in affected and unaffected cartilage. Integrated pathway analysis implicated the involvement of genes related to cell adhesion, extracellular matrix organization, and cell migration in disease progression. Through the integration of gene and protein expression data in human primary chondrocytes, the authors identified molecular markers of microtia progression that were replicated across independent datasets and that have translational potential.