Current Issues With Pediatric Cochlear Implantation.

Cochlear implants (CIs) have demonstrated a clear functional benefit in children with severe-to-profound sensorineural hearing loss (SNHL) and thus have gained wide acceptance for treating deafness in the pediatric population. When evaluating young children for cochlear implantation, there are unique considerations beyond the standard issues addressed during surgery in adults. Because of advances in genetic testing, imaging resolution, CI technology, post-implant rehabilitation, and other factors, issues related to CI surgery in children continue to evolve. Such factors have led to changes in candidacy guidelines, vaccine requirements, and lowering of age requirement for surgery. In addition, differences in the anatomy and physiology of infants require special attention to ensure safety when operating on young children. This review summarizes these issues and provides guidance for surgeons treating children with SNHL.

A Case of Unilateral Simultaneous Preauricular Sinus and Postauricular Sinus in an Adult.

Preauricular sinuses are relatively common congenital anomalies of the soft tissues of the ear. By strict definition, when they connect 2 separate spaces, they are referred to as a preauricular fistula. This clinical entity was first described by Heusinger in 1864. Most preauricular sinuses have a small opening located anterior to the root of the helix. In rare cases, they are found posterior to the tragus, near the crus of the helix, and the ear lobule. The latter is the variant type preauricular sinus, also referred to as the "postauricular sinus," as the sinus tract opens posterior to the auricle. Recurrent infections or persistent discharge may require surgical excision which is ideally performed at a time when there is no inflammation. There are a variety of techniques for excision. Regardless of the surgical approach taken, it is of critical importance to remove the subcutaneous sac completely. We present a very rare case involving the co-occurrence of a preauricular sinus and postauricular sinus in a 33-year-old woman. We report this case with a review of the literature.

Evaluation of Current Triological Society Thesis Trends and Membership Demographics.

OBJECTIVES: (1) Identify the time required for completion, submission, and acceptance of a Triological Thesis and trends for thesis acceptance. (2) Determine the current Triological Society demographics and identify variances based on separated age groups of the current membership. STUDY DESIGN: Retrospective review of The Triological Society database and survey of candidates and fellows. METHODS: Data from the records of all candidates and fellows of the Triological Society were reviewed to determine the number of years from candidate to active fellow status for all members inducted into the Triological Society from 1990 to 2018. In addition, all current candidates, active and senior fellows were surveyed online to capture demographic data and opinions regarding the Triological Society. RESULTS: Since 1990, there has been a steady increase in the number of candidates and theses accepted. Of candidates successfully completing theses, 73% did so within 3 years and 90% within 5 years. Based on the 514 of 809 (64%) active and senior fellows responding to the survey, 83% reported being male and 15% female. Also, 73% reported as Caucasian, 12% Asian, 2% Hispanic, 2% Black, 0% Native American, and 2% Mixed Race. Of the 93 of 178 (52%) active candidates (those authorized to prepare a thesis) responding to the survey, 70% reported as male, 28% female, 58% Caucasian, 17% Asian, 6% Hispanic, 5% Black, 0% Native American, and 3% Mixed Race. CONCLUSIONS: The Triological Society continues to grow, and its membership is becoming more diverse, including more women and wider ethnic diversity. Candidates should plan for submitting their thesis as early as possible as data demonstrates the greatest likelihood of success if done within 3 years. LEVEL OF EVIDENCE: NA Laryngoscope, 133:73-78, 2023.

Pediatric Single-Sided Deafness.

The purpose of this article is to outline the current state of evaluating children with unilateral hearing loss, with significant focus on cochlear implantation, in terms of reviewing the key points of the history, including the duration of deafness, outlining the recommended audiometric testing battery, and discussing issues related to imaging of the auditory system and related anatomy. In addition, a comprehensive and up-to-date summary of outcomes in terms of speech perception, sound localization, and quality of life for both the child with unilateral hearing loss as well as their parent(s) is reported.

A retrospective evaluation of minimally invasive ponto surgery (MIPS) in two pediatric centers.

BACKGROUND: Percutaneous bone anchored hearing systems have been used effectively for over forty years with low rates of complications. Minimally Invasive Ponto Surgery (MIPS) is a surgical technique performed through a puncture hole that has been reported to minimize soft tissue trauma and decrease operative time. Due to it being a relatively new procedure there remains a paucity of pediatric outcomes data. METHODS: Pediatric patients from two tertiary pediatric otolaryngology centers between 2016 and 2019 who underwent MIPS were included in this study. Charts were retrospectively reviewed for indications for surgery, implant and abutment type, overlying skin thickness, skin-to-skin time, Holgers score at three, six and twelve months, revision surgery and time to abutment fitting. RESULTS: Fourteen patients, two with bilateral procedures met inclusion criteria (mean age = 8.07 ± 2.87years). The mean overlying skin thickness was 5.13 ± 3.18mm. 9.44% of visits had an adverse skin reactionOne patient required surgery forskin overgrowth. One implant loss (6.3%) was reported, following trauma to the abutment. Mean MIPS skin to skin times were 12.4 ± 2.6 min, markedly different that the Baha® Attract and Connect which were 56 and 53 min, respectively. CONCLUSION: This study represents the largest pediatric MIPS cohort to date, and our results are similar to published adult studies.

Revision pediatric cochlear implantation in a large tertiary center since 1986.

Objective: To identify the rate of cochlear implantation (CI) re-implantation and assess audiologic outcomes. Methods: Demographic, audiometric, radiographic, and clinical data were collected from the medical records of the first 834 pediatric patients (age < 18) who underwent CI at a tertiary-care center. Results: Reviewing the first 834 pediatric patients who underwent CI between 1986 and 2013, 33 (4%) children have required re-implantation. Seven (0.8%) of these required a second re-implantation, for a total of 40 total revision surgeries (4.8%) and 21.1% of patients who underwent revision required multiple re-implantations. The mean age at initial CI was 3.5 years old, with identification of the failure an average of 2.7 years later (range, 0.1-10.1 years). The most common indications for re-implantation CI were unknown etiology (58%), vendor recall (18%), and trauma (9%). Twenty-three (88.5%) of the 26 patients who underwent only one re-implantation surgery achieved a complete insertion with both procedures. Eleven (91.7%) of 12 patients who had open set speech after their initial procedure maintained this after re-implantation surgery. Eight (38.1%) of 21 patients who did not have open-set speech after their initial implantation achieved open set speech with CI re-implantation. Conclusion: CI re-implantation is not common in the pediatric population. However, given the time-sensitive nature of speech/language development in children, with the right indications, CI re-implantation can be performed safely without compromising audiologic outcomes. However, re-implanted patients have an increased risk they will require re-implantation again in the future.

Labyrinthitis ossificans: how accurate is MRI in predicting cochlear obstruction?

OBJECTIVE: To determine the accuracy of preoperative MRI in predicting cochlear obstruction in pediatric patients with a history of bacterial meningitis. METHODS: A case series with chart review was performed at a tertiary care multidisciplinary cochlear implant program. Forty-five children with hearing loss that resulted from bacterial meningitis were implanted from 1991 to 2006. Twenty-five children had preoperative MRI with high-resolution axial T2-weighted images to assess for cochlear patency. RESULTS: Seventeen of 25 patients (68%) had surgical evidence of cochlear obstruction. Six patients (37.5%) required circummodiolar drill-outs, and one patient (6.25%) underwent placement of a double array cochlear implant. The nine remaining patients (56%) with cochlear obstruction required removal of fibrous tissue or drilling of the inferior basal turn, but did not require manipulation of the ascending basal turn to achieve full electrode insertion. The sensitivity, specificity, and positive and negative predictive value of MRI predicting intraoperative cochlear obstruction with 95 percent confidence intervals was 94.1 percent (71-99), 87.5 percent (47-99), 94.1 percent (71-99) and 87.5 percent (47-99), respectively. CONCLUSION: Preoperative high-resolution T2 MRI may be useful in predicting cochlear obstruction in patients with a prior history of bacterial meningitis.

Promotion of neurite outgrowth and axon guidance in spiral ganglion cells by netrin-1.

OBJECTIVE: To identify the expression of netrin-1, a diffusible chemoattractive molecule, and its receptor, deleted in colorectal carcinoma (DCC), in the developmentally mature inner ear, and to determine its effects on axon length and guidance in cultured auditory neurons. DESIGN: Messenger RNA (mRNA) and protein expression of netrin-1 and DCC were identified in the organ of Corti and spiral ganglion cells using reverse transcription-polymerase chain reaction (RT-PCR) and fluorescence immunohistochemical analysis. In vitro experiments examined the effects of exogenous netrin-1 on spiral ganglion cell axon length. Auditory neurons were cocultured with a cell line secreting netrin-1 to determine the effect on direction of axon extension. SUBJECTS: Young C57 mice and posthatched white leghorn chicks. RESULTS: Netrin-1 and DCC mRNA expression were found in the mouse organ of Corti and spiral ganglion cells by RT-PCR. Application of exogenous netrin-1 led to a dosage-dependent increase in neurite length in cultured spiral ganglion cells. Chick acoustic ganglion cells cocultured with netrin-1-secreting cells demonstrated statistically significant preferential extension toward the source of netrin-1 (P = .04). CONCLUSIONS: Netrin-1 and DCC are expressed in the organ of Corti and spiral ganglion cells of developmentally mature mice. Exogenous netrin-1 promotes dosage-dependent neurite growth in vitro. Mature auditory neurons preferentially direct neurite extension toward netrin-1 released in culture. These findings may lead to the development of strategies to optimize the interface between electrode arrays and spiral ganglion cells, resulting in improved cochlear implant performance.

Role of balloon dilation in the management of adult idiopathic subglottic stenosis.

OBJECTIVES: We evaluated the efficacy of balloon dilation for adjunctive and symptomatic management of isolated idiopathic subglottic stenosis in adults. METHODS: Adults with airway obstruction symptoms classified as idiopathic subglottic stenosis based on history and findings of a single discrete stenotic area on microlaryngoscopy and bronchoscopy were included in this series. Patients who met these criteria underwent dilation with a 10- to 14-mm balloon in a single procedure or in 2 consecutive dilations within 7 days. The patients were followed for up to 30 months after dilation. RESULTS: Six patients met the criteria. One of the 6 had prior laser treatments and a cricotracheal resection. One patient had a previous scar band lysis procedure. The remaining 4 patients had no prior procedures. The airway sizes prior to dilation ranged from a 2.5 endotracheal tube to a 5.0 endotracheal tube. In all cases the airway was dilated to 2.0 to 3.5 endotracheal tube sizes larger than the initial size. To date, 4 patients have been followed for 10 to 30 months without symptoms of recurrent airway stenosis. One patient was symptom-free for 22 months, then presented with progressive airway difficulty following an upper respiratory tract infection, and has undergone a repeat dilation. No patients had adverse effects or complications from the procedure. CONCLUSIONS: Balloon dilation of idiopathic subglottic stenosis in adults is a relatively safe and effective method to manage this disease entity for cases of isolated and discrete lesions. Patients who underwent a single procedure have remained symptom-free for up to 30 months after balloon dilation.

Discovery of Tirasemtiv, the First Direct Fast Skeletal Muscle Troponin Activator.

The identification and optimization of the first activators of fast skeletal muscle are reported. Compound 1 was identified from high-throughput screening (HTS) and subsequently found to improve muscle function via interaction with the troponin complex. Optimization of 1 for potency, metabolic stability, and physical properties led to the discovery of tirasemtiv (25), which has been extensively characterized in clinical trials for the treatment of amyotrophic lateral sclerosis.

Clinical outcomes following cochlear implantation in children with inner ear anomalies.

OBJECTIVE: A significant proportion of children with congenital hearing loss who are candidates for cochlear implants (CIs) may have inner ear malformations (IEMs). Surgical and speech outcomes following CI in these children have not been widely reported. METHODS: The charts of children who were evaluated for a CI between 1/1/1986 and 12/31/2014 at a university-based tertiary level pediatric cochlear implant center were reviewed. Principal inclusion criteria included (i) age 1-18 years, (ii) history of bilateral severe to profound sensorineural hearing loss, and (iii) limited benefit from binaural amplification. Exclusion criteria included (i) underlying diagnosis of neurodevelopmental disorder and (ii) lack of follow up for speech assessment if a CI was performed. The following outcome measures were reviewed: (i) imaging findings with magnetic resonance imaging or high resolution computed tomography, (ii) intraoperative complications, and (iii) speech perception categorized as the ability to perceive closed set, open set, or none. RESULTS: The prevalence of IEMs was 27% (102 of 381), of which 79% were bilateral. Cochlear dysplasia accounted for 30% (40 of 136) of the anomalies. Seventy-eight of the 102 patients received a CI (78%). Surgery was noted to be challenging in 24% (19 of 78), with a perilymphatic gusher being the most common intraoperative finding. Cochlear dysplasia, vestibular dysplasia and cochlear nerve hypoplasia were associated with poor speech perception (open OR closed set speech recognition scores, 0-23%), although the outcomes in children with enlarged vestibular aqueduct were similar to those of children with normal inner ear anatomy (65%). CONCLUSIONS: Cochlear implantation is safe in children with IEMs. However, the speech perception outcomes are notably below those of patients with normal anatomy, with the exception of when an enlarged vestibular aqueduct is present.

Transcanal Endoscopic Ear Surgery for the Management of Congenital Ossicular Fixation.

OBJECTIVES: 1) To describe the technique for transcanal endoscopic management of congenital ossicular chain fixation. 2) To highlight the utility and outcomes of the endoscopic approach for management of congenital ossicular fixation. STUDY DESIGN: Retrospective patient series. SETTING: Academic tertiary pediatric hospital. PATIENTS: Pediatric patients (age 6-12) undergoing transcanal endoscopic management of congenital ossicular fixation from May 2014 to December 2014. INTERVENTIONS: A transcanal endoscopic approach was used in eight procedures. Ossicular chain pathology was managed with either mobilization, ossiculoplasty with a stapes prosthesis, or incus interposition. MAIN OUTCOME MEASURES: Pure-tone averages, speech reception thresholds, and speech discrimination scores were recorded pre- and postoperatively for each subject. Preoperative computed tomography evaluations were compared to intraoperative findings for each subject. RESULTS: An improvement in the pure-tone average, as well as air-bone gap, was noted after six of eight procedures. No patients experienced a complication or a reduction in their bone conduction hearing. The chorda tympani nerve was preserved in all eight patients. Conversion to open approach was not necessary for any of the eight procedures performed. CONCLUSION: The transcanal endoscopic approach was successful in improving hearing in pediatric patients with congenital ossicular fixation that involves any of the three ossicles. An endoscopic transcanal approach provides an alternative method to manage congenital ossicular pathology with the advantage of providing excellent visualization and the avoidance of a postauricular incision.

Ephrin A2 may play a role in axon guidance during hair cell regeneration.

OBJECTIVE: Hair cell regeneration in the avian cochlea is accompanied by frequency specific reinnervation and recovery of physiologic function. The molecular cues that guide ganglion cells to tonotopically appropriate new hair cells have not been identified. We investigated the potential of ephrin A2 in this process. STUDY DESIGN: Ephrin A2 expression was characterized in acoustic ganglion cells of normal and gentamicin-treated early post hatch chicks. METHODS: Ephrin A2 expression was determined by Western analysis of total protein isolated from acoustic ganglia in normal animals. Protein localization was characterized by fluorescence immunohistochemistry in sections of acoustic ganglia of normal and gentamicin treated animals. Patterns of ephrin A2 expression in acoustic ganglia were determined and quantified during hair cell regeneration. RESULTS: Ephrin A2 expression was found in acoustic ganglia by Western analysis. Localization of this protein by immunofluorescence revealed its presence in acoustic ganglion cells in normal chicks. After gentamicin treatment, ephrin A2 expression was lost in a subset of acoustic ganglion cells. The spatial and temporal pattern of ephrin A2 loss coincides with the pattern of hair cell loss and regeneration. CONCLUSIONS: The changes in ephrin A2 immunoreactivity in acoustic ganglion cells during cochlear damage and regeneration suggests that ephrin A2 may be involved in the guidance of ganglion cells to tonotopically appropriate hair cell targets during regeneration. Ephrin A2 in hair cell regeneration.

The Impact of Postmeningitic Labyrinthitis Ossificans on Speech Performance After Pediatric Cochlear Implantation.

OBJECTIVE: 1) To characterize pediatric cochlear implant performance in patients with hearing loss secondary to bacterial meningitis. 2) To evaluate performance differences in patients with and without labyrinthitis ossificans (LO). STUDY DESIGN: Retrospective case review. SETTING: A large university-based multidisciplinary cochlear implant program. PATIENTS: Forty-nine patients with hearing loss from bacterial meningitis who received cochlear implants from 1991 to 2011. Thirty-nine patients had adequate data for analysis. INTERVENTION: Cochlear implantation with postoperative performance evaluation. MAIN OUTCOME MEASURE(S): Speech perception category (SPC). RESULTS: Nineteen (48.7%) patients had intraoperative evidence of LO. Fourteen patients (70.0%) without LO compared with seven (36.8%) with LO developed open-set speech after implantation. There was a trend toward better postimplant SPC outcomes in patients without LO that did not reach statistical significance (p = 0.17). The presence of LO negatively correlated with classroom placement (p < 0.05). Analysis of each group individually demonstrated statistically significant improvement in pre- versus postimplant SPC outcomes (p < 0.001). CONCLUSION: The presence of LO may negatively affect performance in pediatric patients receiving a cochlear implant for hearing loss secondary to bacterial meningitis.

Ephrins and Ephs in cochlear innervation and implications for advancing cochlear implant function.

OBJECTIVES/HYPOTHESIS: Determine if the neuronal pathfinding cues resulting from Eph/ephrin interaction in the inner ear play a role in establishing the tonotopic innervation of the cochlea. STUDY DESIGN: Protein expression of Ephs and ephrins was evaluated in the inner ear of mice and chicks. Subsequently, in vitro, in vivo, and functional electrophysiologic studies were performed to indicate that Ephs and ephrins play a role regulating the normal innervation patterns in the mouse inner ear. METHODS: Eph and ephrin protein expression was identified in the inner ear by western blotting and localized by fluorescence immunohistochemistry and X-gal staining. Eph/ephrin effects on neurite outgrowth was assessed via co-culture with EphB2 expressing COS-1 cells. Anatomic effects of disrupting Eph/ephrin signaling on cochlear innervation were determined with lipophilic dye tracing and functional effects with auditory brainstem response (ABR). RESULTS: Expression of several different Ephs and ephrins were found in the inner ear of chicks and mice. The changes in ephrin-A2 immunoreactivity after gentamicin ototoxicity coincide with the spatio-temporal pattern of hair cell loss and regeneration in the chick cochlea. EphB2 inhibited outgrowth of spiral ganglion cell neurites. Knockout mice with null function of EphB1, EphB2, and EphB3 demonstrated abnormal inner ear innervation and elevated ABR thresholds, indicating hearing loss. CONCLUSIONS: Ephrin-A2 may be involved in the guidance of ganglion cells to hair cells in the chick. Disruption of Eph/ephrin signaling results in abnormal innervation and hearing loss, suggesting that these proteins play a role in establishing normal innervation patterns in the mouse cochlea. LEVEL OF EVIDENCE: NA

Asymmetry in semicircular canal diameters may account for circling behavior in EphB-deficient mice.

OBJECTIVES/HYPOTHESIS: Determine if differences in right and left semicircular size account for phenotypic behavior, indicating vestibulopathy in EphB deficient mice. STUDY DESIGN: The diameters of the superior semicircular canals (SCC) were measured. The differences in the right and left superior SCC diameters were analyzed in homozygous EphB2 and EphB3 double knockout mice known to have head bobbing and circling behavior. Results were compared to similar analysis in wild type controls that displayed no signs of vestibulopathy. METHODS: Axial frozen sections through the superior (SCC) were analyzed by light microscopy; and the diameters of the left and right canals were measured in µm for both EphB2 and EphB3 double knockout mice, as well as in wild type control mice. The differences in diameter between the left and right superior SCC was determined for each animal. RESULTS: Overall, the EphB2 and EphB3 double knockout mice had smaller superior SCC diameters compared to wild type (109.0±21.4 µm vs. 185.0±5.2 µm (P<0.0001). The mean difference in left and right diameter of the superior SCC of EphB2/EphB3 double knockout mice was 29.0±8.7 µm; in wild-type controls this difference was 6.0±5.1 µm (P=0.002). In addition, the direction of circling appeared to be independent of the laterality of the smaller (or larger) superior SCC. CONCLUSION: Mice deficient in EphB2/EphB3 signaling have smaller superior SCC and asymmetry in lumen sizes between the left and right sides. The laterality of the larger versus smaller is not correlated with the direction of circling behavior. LEVEL OF EVIDENCE: N/A.

Ciprofloxacin 0.3% + dexamethasone 0.1% for the treatment for otitis media.

INTRODUCTION: Ciprofloxacin 0.3% with dexamethasone 0.1% (ciprofloxacin/dexamethasone) is an ototopical preparation for acute otitis externa, otorrhea with tympanostomy tubes, and is frequently used to treat chronic suppurative otitis media (CSOM). The advantage of topical therapy is the ability to deliver higher concentration of antibiotics to the treatment site when compared with oral or parenteral antibiotics. The delivery of a high concentration of antibiotics significantly decreases treatment failure and makes the development of resistant organisms unlikely. Previous ototopical preparations contained antibiotics such as aminoglycosides that are known to be ototoxic making treatment of otic infections without an intact tympanic membrane difficulty. AREAS COVERED: A literature search of PubMed was performed as the basis for a literature-based discussion on the clinical efficacy of ciprofloxacin/dexamethasone compared to oral antibiotics and ototopical therapy without a steroid component. The potential ototoxicity of ototopical therapies is discussed, including evidence demonstrating the lack of ototoxicity of fluoroquinolone and dexamethasone containing drops. EXPERT OPINION: Because multiple studies have demonstrated that fluoroquinolones are not ototoxic, fluoroquinolone ototopical drops should be a first-line treatment for otorrhea without an intact membrane. The addition of dexamethasone 0.1% to ciprofloxacin 0.3% has been shown to decrease granulation tissue, improve clinical cure and achieve greater rates of bacterial eradication when compared to ciprofloxacin 0.3% alone.

Pediatric stapedectomy: does cause of fixation affect outcomes?

OBJECTIVE: To compare outcomes of stapedectomy in patients with congenital stapes fixation versus juvenile otosclerosis. METHODS: A retrospective chart review was performed from January 1, 1999 until January 1, 2011 to identify patients under 18 years old who underwent a stapedectomy. Age, gender, pre- and postoperative audiograms, intraoperative findings including etiology of stapes fixation, prosthesis type, and complications were recorded. RESULTS: Twenty-two children were identified who had undergone a stapedectomy (two patients underwent sequential bilateral surgery) resulting in a total of 24 ears. The cause of fixation included juvenile otosclerosis (n=7) and congenital stapes fixation (n=17). The overall mean pre-operative air-bone gap (ABG) was 34.7 dB (SD: 13.5) compared to a postoperative mean ABG of 9.0 (SD: 9.3) (p<0.001). The mean postoperative ABG of 9.6 (SD: 10.5) in the congenital stapes fixation group was similar to the mean postoperative ABG of 7.2dB (SD: 5.4) in children with juvenile otosclerosis (p=0.6). Two patients developed delayed profound sensorineural hearing loss approximately two weeks after surgery. One patient with profound sensorineural hearing loss recovered to a profound mixed hearing loss with a speech discrimination score of 80%. CONCLUSIONS: Pediatric stapedectomy has comparable results to stapedectomy in adults regardless of the cause of stapes fixation; however, delayed sensorineural hearing loss may be higher in the pediatric population.

Characterization of the larynx in ephrin-B2 knockout mice: a novel animal model for laryngeal clefts.

OBJECTIVE: To identify and classify laryngeal clefts in a novel mouse model. DESIGN: In vivo animal study. SETTING: Academic research laboratory. SUBJECTS: 129/CD1 mice with the ephrin-B2 gene disrupted by the ß-galactosidase (lacZ) gene were humanely killed at embryonic day 18 (E18) and evaluated for the presence and characterization of a laryngeal cleft. Homozygous and heterozygous lacZ knockout mice as well as wild-type littermates were evaluated. MAIN OUTCOME MEASURES: Microsurgical dissection of the oral cavity and pharynx allowed for a pseudoendoscopic view of the larynx to determine the presence or absence of a cleft. The specimens were also histologically sectioned and examined for characterization and classification of the cleft. RESULTS: A laryngeal cleft was identified in 12 of 27 ephrin-B2 homozygous lacZ knockout mice (44%). Laryngeal clefts were not identified in heterozygous ephrin-B2 knockout mice or in wild-type littermates. CONCLUSIONS: Disruption of ephrin-B2 reverse signaling results in laryngeal clefts in lacZ knockout mice. This presents a novel mouse model in which future investigations into etiology of laryngeal clefts may be examined.