A randomised controlled trial of surgery for glue ear.

OBJECTIVE--To assess the effect of five different surgical treatments for glue ear (secretory otitis media) on improvement in hearing and, assuming one or more treatments to be effective, to identify the appropriate indications for surgery. DESIGN--Randomised controlled trial of children receiving (a) adenoidectomy, bilateral myringotomy, and insertion of a unilateral grommet; (b) adenoidectomy, unilateral myringotomy, and insertion of a unilateral grommet; (c) bilateral myringotomy and insertion of a unilateral grommet; and (d) unilateral myringotomy and insertion of a grommet. Children were followed up at seven weeks, six months, 12 months, and 24 months by symptom history and clinical investigations. SETTING--Otolaryngology department in an urban hospital. PATIENTS--149 Children aged 4-9 years who were admitted for surgery for glue ear and who had no history of previous operations on tonsils, adenoids, or ears and no evidence of sensorineural deafness. Inadequate follow up information on levels of hearing and on middle ear function was obtained from 22. MAIN OUTCOME MEASURES--Mean hearing loss (dB) of the three worst heard frequencies between 250 and 4000 Hz, results of impedance tympanometry, and parental views on their child''s progress. RESULTS--In the 127 children for whom adequate information was available ears in which a grommet had been inserted performed better in the short term (for at least six months) than those in which no grommet had been inserted, irrespective of any accompanying procedure. Most of the benefit had disappeared by 12 months. Adenoidectomy produced a slight improvement that was not significant, though was sustained for at least two years. The ears of children who had had an adenoidectomy with myringotomy and grommet insertion, however, continued to improve so that two years after surgery about 50% had abnormal tympanometry compared with 83% of those who had had only myringotomy and grommet insertion, and 93% of the group that had had no treatment. Logistic regression analyses identified preoperative hearing level as the single best predictor of good outcome from surgery. Other variables contributed little additional predictive power. CONCLUSIONS--If the principal objective of surgery for glue ear is to restore hearing then our study shows that insertion of grommets is the treatment of choice. The addition of an adenoidectomy will increase the likelihood of restoration of normal function of the middle ear but will not improve hearing. When deciding appropriate indications for surgery, a balance has to be made between performing unnecessary operations and failing to treat patients who might benefit from surgical intervention. Preoperative audiometry scores might be the best predictor in helping to make this decision.     

Chronic otitis media with effusion (glue ear) and adenotonsillectomy: prospective randomised controlled study.

A prospective study was conducted of the effects of adenoidectomy and adenotonsillectomy on established otitis media with effusion unresponsive to medical treatment. The operations were performed at random with a controlled no surgery group on a cohort of 103 children with the condition and the results assessed six weeks, three months, six months, nine months, and one year later. After adenoidectomy the rate of resolution of the condition increased from 39% at six weeks to 72% at one year; and after adenotonsillectomy the rate increased from 59% at six weeks to 62% at one year. In the no surgery group the rate increased from 16% at six weeks to 26% at one year. Compared with the no surgery group the effect of adenoidectomy alone at one year was highly significant (p less than 0.001), and similarly the effect of adenotonsillectomy was significant (p less than 0.01). There was, however, no increased benefit from the addition of tonsillectomy compared with adenoidectomy alone. Thus there was resolution of 36-46% of chronic effusions as a result of adenoidectomy.     

The Protective Effect of Adenoidectomy on Pediatric Tympanostomy Tube Re-Insertions: A Population-Based Birth Cohort Study

Objectives

Adenoidectomy in conjunction with tympanostomy tube insertion for treating pediatric otitis media with effusion and recurrent acute otitis media has been debated for decades. Practice differed surgeon from surgeon. This study used population-based data to determine the protective effect of adenoidectomy in preventing tympanostomy tube re-insertion and tried to provide more evidence based information for surgeons when they do decision making.

Study Design

Retrospective birth cohort study.

Methods

This study used the National Health Insurance Research Database for the period 2000–2009 in Taiwan. The tube reinsertion rate and time to tube re-insertion among children who received tympanostomy tubes with or without adenoidectomy were compared. Age stratification analysis was also done to explore the effects of age.

Results

Adenoidectomy showed protective effects on preventing tube re-insertion compared to tympanostomy tubes alone in children who needed tubes for the first time (tube re-insertion rate 9% versus 5.1%, p = 0.002 and longer time to re-insertions, p = 0.01), especially those aged over 4 years when they had their first tube surgery. After controlling the effect of age, adenoidectomy reduced the rate of re-insertion by 40% compared to tympanostomy tubes alone (aHR: 0.60; 95% CI: 0.41–0.89). However, the protective effect of conjunction adenoidectomy was not obvious among children with a second tympanostomy tube insertion. Children who needed their first tube surgery at the age 2–4 years were most prone to have tube re-insertions, followed by the age group of 4–6 years.

Conclusions

Adenoidectomy has protective effect in preventing tympanostomy tube re-insertions compared to tympanostomy tubes alone, especially for children older than 4 years old and who needed tubes for the first time. Nonetheless, clinicians should still weigh the pros and cons of the procedure for their pediatric patients.     

The effect of palate repair on otitis media with effusion.

Cleft palate in children is very frequently associated with otitis media with effusion. In this prospective study of 150 cleft palate children aged between 2 and 18 months, the prevalence of otitis media with effusion at myringotomy before palate repair was 92 percent. Otoscopic and tympanometric follow-up assessments for 140 children indicate that there is minimal improvement in middle ear status after palate repair. The condition is persistent in 70 percent of children up to 4 years of age. Furthermore, there is no evidence that age at repair or type of cleft is influential. These findings have implications for otologic management of cleft palate children. Early routine unilateral ventilation to ensure adequate hearing but minimize the morbidity of ventilation tubes is advocated.     

Characteristics of the hearing loss in unilateral cleft lip and palate-influence on communication

Etiology of otitis media with effusion (OME) is still unclear and often described as multi-factorial. It is very usual finding in cleft palate population. We tested relationship between the hearing level, audiometric frequencies, aging and ear side in unilateral cleft lip and palate 101 children (UCLP) and subgroups of left (UCLP)(L) and right cleft side (UCLP)(R). Group of left ears is prone to higher frequency and more severe hearing disturbances than groups of right ears, with less chance of normalizing hearing level with aging. Characteristics of hearing loss level and its improvement, in UCLP children depend of cleft type, ear side and age group.     

Glue ear: the new dyslexia?

Several factors have led to the current epidemic of surgery for glue ear in children, including the widespread introduction of audiometry; greater recognition of the presence of fluid in the middle ear by general practitioners; the availability of more otolaryngologists; and technical advances such as the availability of antibiotics to treat postoperative infections and of flanged tympanostomy tubes (grommets). The need of surgeons to fill the vacuum caused by the decline in the number of adenotonsillectomies, and the fact that a diagnosis of glue ear legitimises the continued use of these operations, may also have contributed to the increase. Finally, glue ear may provide parents with a medical explanation of their children''s poor educational performance, as the term dyslexia did in the past. The high social and public costs of this operation demand a reappraisal of its increasing use.     

儿童腺样体肥大程度与分泌性中耳炎发生的相关性研究(英文)

目的:探讨儿童腺样体肥大程度与分泌性中耳炎发生及预后的相关性,指导临床医师对分泌性中耳炎作出早期诊断和治疗。方法:239例住院手术切除腺样体的儿童,常规行鼻咽侧位片、声导抗检查;部分伴耳部症状、声导抗显示C型曲线或查体可疑鼓室积液征者行颞骨CT检查或术中行鼓室穿刺。经统计学分析,比较分泌性中耳炎与腺样体肥大程度及咽鼓管咽口情况的相关性。结果:在239例腺样体肥大儿童中,经鼓室穿刺证实合并分泌性中耳炎者34例(63耳,14.2%),其中鼓室曲线呈B型者33耳(52.4%),C型(-200 dapa)者10耳(15.9%),C型(-200 dapa)者20耳(31.7%)。结果表明分泌性中耳炎的发生与腺样体肥大程度及咽鼓管园枕受压迫的程度呈正相关。结论:声导抗检查不能作为分泌性中耳炎诊断的金标准,必要时可行颞骨CT明确诊断;对腺样体肥大伴分泌性中耳炎的儿童鼻内镜下腺样体切除为其主要疗法,配合鼓室穿刺多可治愈,对反复发作的分泌性中耳炎行鼓室置管术,避免术后并发症的发生。     

Treatment of Middle Ear Ventilation Disorders: Sheep as Animal Model for Stenting the Human Eustachian Tube – A Cadaver Study

Eustachian tube disorders can lead to chronic otitis media with consecutive conductive hearing loss. To improve treatment and to develop new types of implants such as stents, an adequate experimental animal model is required. As the middle ear of sheep is known to be comparable to the human middle ear, the dimensions of the Eustachian tube in two strains of sheep were investigated. The Eustachian tube and middle ear of half heads of heathland and blackface sheep were filled with silicone rubber, blended with barium sulfate to induce X-ray visibility. Images were taken by digital volume tomography. The tubes were segmented, and a three-dimensional model of every Eustachian tube was generated. The lengths, diameters and shapes were determined. Additionally, the feasibility of endoscopic stent implantation and fixation was tested in cadaver experiments. The length of the tube between ostium pharyngeum and the isthmus and the diameters were comparable to published values for the human tube. The tube was easily accessible through the nose, and then stents could be implanted and fixed at the isthmus. The sheep appears to be a promising model for testing new stent treatments for middle ear ventilation disorders.     

Complications of tonsillectomy and adenoidectomy in 9409 children observed overnight.

In attempts to minimize the cost of health care, physicians are reducing the duration of hospital stay. Traditionally, at the Hospital for Sick Children, Toronto, otherwise healthy children undergoing adenoidectomy, tonsillectomy or adenotonsillectomy have been admitted the morning of surgery and discharged from hospital at 7 am the next day. The nursing records of 9409 patients aged 17 years or less who were managed in this way between 1980 and 1984 were reviewed to determine the occurrence of complications during the observation period. A total of 202 patients (2.15%) bled during the observation period. Of the 202, 6 (0.06% of all the patients) required a second general anesthetic for hemostasis; 1 of these 6 patients and 5 others required blood transfusions. Discharge was delayed for 42 patients (0.45% of all the patients) because of postoperative bleeding and for 57 patients (0.6%) for a variety of other reasons. Delayed discharge for reasons other than hemorrhage was more frequent among children less than 2 years of age and those over 12 years of age. The authors concluded that children undergoing adenoidectomy could safely be discharged the same day after 6 hours of observation following surgery. However, as a substantial number of children bled from the tonsillar fossa more than 6 hours after surgery, the efficacy of periodic examination of the oral cavity during the observation period in reducing the rate of hemorrhage after 6 hours must be evaluated before a same-day discharge program is established for children undergoing adenotonsillectomy.     

Parent-Reported Otorrhea in Children with Tympanostomy Tubes: Incidence and Predictors

Purpose

Although common in children with tympanostomy tubes, the current incidence of tympanostomy tube otorrhea (TTO) is uncertain. TTO is generally a sign of otitis media, when middle ear fluid drains through the tube. Predictors for otitis media are therefore suggested to have predictive value for the occurrence of TTO.

Objective

To determine the incidence of TTO and its predictors.

Methods

We performed a cohort study, using a parental web-based questionnaire to retrospectively collect data on TTO episodes and its potential predictors from children younger than 10 years of age with tympanostomy tubes.

Results

Of the 1,184 children included in analyses (total duration of time since tube placement was 768 person years with a mean of 7.8 months per child), 616 children (52%) experienced one or more episodes of TTO. 137 children (12%) had TTO within the calendar month of tube placement. 597 (50%) children had one or more acute TTO episodes (duration <4 weeks) and 46 children (4%) one or more chronic TTO episodes (duration ≥4 weeks). 146 children (12%) experienced recurrent TTO episodes. Accounting for time since tube placement, 67% of children developed one or more TTO episodes in the year following tube placement. Young age, recurrent acute otitis media being the indication for tube placement, a recent history of recurrent upper respiratory tract infections and the presence of older siblings were independently associated with the future occurrence of TTO, and can therefore be seen as predictors for TTO.

Conclusions

Our survey confirms that otorrhea is a common sequela in children with tympanostomy tubes, which occurrence can be predicted by age, medical history and presence of older siblings.     

Flexible Integration of Laser Myringotomy and Ventilation Tube for Bilateral Otitis Media with Effusion: Analysis of Laser Tympanostomy versus Ventilation Tube

Background

The aim of this study was to evaluate the efficacy of laser myringotomy (LM) compared to ventilation tube (VT), and to assess the clinical success criteria of LM-assisted VT insertion as the flexible alternatives avoiding GA for the treatment of bilateral consistent otitis media with effusion (OME).

Methods and Findings

LM under topical anesthesia was followed by VT insertion in cooperative children using Acuspot® 712 CO2 laser micromanipulator attached microscope. Sixty children failed VT and bilateral laser tympanostomy was done (group LL), and 130 children tolerated VT on one side but LM on the other side (group LV). The efficacy of LM was compared to VT regarding recurrent effusion and reoperation as the outcome measure; firstly, by ear-to-ear matched pair analysis in LV, and secondly between LL vs. LV. Long-term outcome was compared to control group who received both VT under GA (group GAVT) regarding the outcome of additional VT and GA.

Results

The effectiveness of LM per ear was equivocal as 46.9% and 40.8% in LV and LL respectively; but the effectiveness per children was further lower in LL as 28.3%, which was a limitation of LM for bilateral OME. LL required reoperation in 71.7% mostly requiring impending GA in 51.7% within 4.7 months, thus was a controversial treatment. But LV required GA in 20.8% during the 27.2 months long-term follow-up, which was second set of VT and adenoidectomy that were also comparably required in GAVT control with multiple GA.

Conclusion

Standard GAVT was more recommended for bilateral OME than bilateral LM (LL) in our practice. But LM was selectively effective for some children, that combined approach with LM plus VT provided comparable period to outgrow OME as effectively as GAVT, when LM was supplemented with one VT side with recovered hearing.     

Relationship between Audiometric slope and tinnitus pitch in tinnitus patients: insights into the mechanisms of tinnitus generation

Background

Different mechanisms have been proposed to be involved in tinnitus generation, among them reduced lateral inhibition and homeostatic plasticity. On a perceptual level these different mechanisms should be reflected by the relationship between the individual audiometric slope and the perceived tinnitus pitch. Whereas some studies found the tinnitus pitch corresponding to the maximum hearing loss, others stressed the relevance of the edge frequency. This study investigates the relationship between tinnitus pitch and audiometric slope in a large sample.

Methodology

This retrospective observational study analyzed 286 patients. The matched tinnitus pitch was compared to the frequency of maximum hearing loss and the edge of the audiogram (steepest hearing loss) by t-tests and correlation coefficients. These analyses were performed for the whole group and for sub-groups (uni- vs. bilateral (117 vs. 338 ears), pure-tone vs. narrow-band (340 vs. 115 ears), and low and high audiometric slope (114 vs. 113 ears)).

Findings

For the right ear, tinnitus pitch was in the same range and correlated significantly with the frequency of maximum hearing loss, but differed from and did not correlate with the edge frequency. For the left ear, similar results were found but the correlation between tinnitus pitch and maximum hearing loss did not reach significance. Sub-group analyses (bi- and unilateral, tinnitus character, slope steepness) revealed identical results except for the sub-group with high audiometric slope which revealed a higher frequency of maximum hearing loss as compared to the tinnitus pitch.

Conclusion

The study-results confirm a relationship between tinnitus pitch and maximum hearing loss but not to the edge frequency, suggesting that tinnitus is rather a fill-in-phenomenon resulting from homeostatic mechanisms, than the result of deficient lateral inhibition. Sub-group analyses suggest that audiometric steepness and the side of affected ear affect this relationship. Future studies should control for these potential confounding factors.     

Delayed detection of congenital hearing loss in high risk infants.

OBJECTIVE--To examine the methods used to investigate children at high risk of congenital hearing impairment, and to see whether the introduction of evoked response audiometry has reduced the mean age at which hearing loss is identified. DESIGN--Clinicians who notified children to the national congenital rubella surveillance programme were asked retrospectively to complete a questionnaire examining the methods used to identify hearing impairment and the age at testing in two consecutive five year cohorts. The presence or absence of hearing loss was confirmed by obtaining the results of audiometric evaluations and, whenever possible, a recent pure tone audiogram. SETTING--The United Kingdom. PATIENTS--Children notified to the national congenital rubella surveillance programme and born in 1978-87 in whom IgM specific for rubella was detected shortly after birth. MAIN OUTCOME MEASURES--The age at which hearing loss was identified and the degree of loss in decibels at 250, 500, 1000, 2000, and 4000 Hz measured by pure tone audiometry. RESULTS--61 (52%) Of 117 children born in 1978-82 had a hearing impairment of 40 dB or greater in both ears. The mean loss was 93 dB. In the following five years 75 (47%) of 159 children had impaired hearing, their mean loss being 96 dB. The age at which the hearing loss was confirmed decreased from 11.6 to 9.8 months as a result of earlier auditory evoked response testing. Nevertheless, only eight (13%) of the children with hearing impairment born in 1978-82 and 16 (21%) of those born in 1983-7 had these tests performed in the first six months of life. CONCLUSIONS--Unacceptable delays in identifying hearing loss occurred in this high risk group because of failure to arrange auditory evoked response testing in early infancy. Evoked response audiometry is sensitive and specific and should be undertaken within the first few months of life for all infants known to be at risk of sensorineural hearing loss.     

Ectopic mineralization in the middle ear and chronic otitis media with effusion caused by RPL38 deficiency in the Tail-short (Ts) mouse

Inflammation of the middle ear cavity (otitis media) and the abnormal deposition of bone at the otic capsule are common causes of conductive hearing impairment in children and adults. Although a host of environmental factors can contribute to these conditions, a genetic predisposition has an important role as well. Here, we analyze the Tail-short (Ts) mouse, which harbors a spontaneous semi-dominant mutation that causes skeletal defects and hearing loss. By genetic means, we show that the Ts phenotypes arise from an 18-kb deletion/insertion of the Rpl38 gene, encoding a ribosomal protein of the large subunit. We show that Ts mutants exhibit significantly elevated auditory-brain stem response thresholds and reduced distortion-product otoacoustic emissions, in the presence of normal endocochlear potentials and typical inner ear histology suggestive of a conductive hearing impairment. We locate the cause of the hearing impairment to the middle ear, demonstrating over-ossification at the round window ridge, ectopic deposition of cholesterol crystals in the middle ear cavity, enlarged Eustachian tube, and chronic otitis media with effusion all beginning at around 3 weeks after birth. Using specific antisera, we demonstrate that Rpl38 is an ～8-kDa protein that is predominantly expressed in mature erythrocytes. Finally, using an Rpl38 cDNA transgene, we rescue the Ts phenotypes. Together, these data present a previously uncharacterized combination of interrelated middle ear pathologies and suggest Rpl38 deficiency as a model to dissect the causative relationships between neo-ossification, cholesterol crystal deposition, and Eustachian tubes in the etiology of otitis media.     

Management of Chronic Middle Ear Effusion

Management of chronic middle ear effusion must center around the reestablishment of normal eustachian tube function. If fluid does not clear with medical management, aspiration becomes necessary. A prosthetic eustachian tube is placed in the tympanic membrane in order to artificially ventilate the middle ear space while primary etiologic factors are being corrected.Unless recurrent or chronic ear disease of this nature is diligently treated, progressive damage may bring about irreversible hearing loss and the potentially dangerous disease, cholesteatoma of the ear.     

HIF-VEGF pathways are critical for chronic otitis media in Junbo and Jeff mouse mutants

Otitis media with effusion (OME) is the commonest cause of hearing loss in children, yet the underlying genetic pathways and mechanisms involved are incompletely understood. Ventilation of the middle ear with tympanostomy tubes is the commonest surgical procedure in children and the best treatment for chronic OME, but the mechanism by which they work remains uncertain. As hypoxia is a common feature of inflamed microenvironments, moderation of hypoxia may be a significant contributory mechanism. We have investigated the occurrence of hypoxia and hypoxia-inducible factor (HIF) mediated responses in Junbo and Jeff mouse mutant models, which develop spontaneous chronic otitis media. We found that Jeff and Junbo mice labeled in vivo with pimonidazole showed cellular hypoxia in inflammatory cells in the bulla lumen, and in Junbo the middle ear mucosa was also hypoxic. The bulla fluid inflammatory cell numbers were greater and the upregulation of inflammatory gene networks were more pronounced in Junbo than Jeff. Hif-1α gene expression was elevated in bulla fluid inflammatory cells, and there was upregulation of its target genes including Vegfa in Junbo and Jeff. We therefore investigated the effects in Junbo of small-molecule inhibitors of VEGFR signaling (PTK787, SU-11248, and BAY 43-9006) and destabilizing HIF by inhibiting its chaperone HSP90 with 17-DMAG. We found that both classes of inhibitor significantly reduced hearing loss and the occurrence of bulla fluid and that VEGFR inhibitors moderated angiogenesis and lymphangiogenesis in the inflamed middle ear mucosa. The effectiveness of HSP90 and VEGFR signaling inhibitors in suppressing OM in the Junbo model implicates HIF-mediated VEGF as playing a pivotal role in OM pathogenesis. Our analysis of the Junbo and Jeff mutants highlights the role of hypoxia and HIF-mediated pathways, and we conclude that targeting molecules in HIF-VEGF signaling pathways has therapeutic potential in the treatment of chronic OM.     

Auditory neuropathy: a report on three cases with early onsets and major neonatal illnesses

We report 3 children without any brainstem auditory evoked potential (BAEP) neural component who all retained isolated cochlear microphonic potentials as well as click-evoked otoacoustic emissions. Two of them demonstrated only moderately impaired audiometric thresholds. These features correspond to a peculiar pattern of auditory dysfunction recently coined `auditory neuropathy'. In contrast with the published previous cases of auditory neuropathy presenting with an acquired hearing deficit as children or young adults, all 3 children had a history of major neonatal illness and the auditory neuropathy was already demonstrated in the first months of their lives.     

Estimation of hearing in patients with end stage renal failure being peritoneally dialyzed with and without furosemide in the dialysis fluid]

The purpose of our study was to estimate hearing state and effect of intraperitoneal administration of furosemide on an organ of hearing in the patients with end-stage renal failure being treated with intermittent peritoneal dialysis. Ten patients divided into two groups, were observed for three months. A weekly dosage of 1.2-2.0 g of furosemide was administered to the patients of first group while the patients of second group were not given furosemide. Based upon the studies, which had been carried out by pure tone audiometry method and Fowler's test and Belesy's audiometry, it was found the lesion of hearing, mainly in the range of higher frequency, having a character of cochlear hypoacusia. The further lesion of hearing was not seen within three months of regular treatment with intermittent peritoneal dialysis. The audiometric studies which had been carried out in different stages of treatment, did not show ototoxicity influence of furosemide added to dialysis fluid.     

Middle-Ear Disease in Indians of the Mount Currie Reservation,British Columbia

Complete otological examinations, including audiograms, were carried out on 504 British Columbia Indians of the Mount Currie Reservation. Of these, 79 were found to have evidence of current middle ear pathology, while 226 were known to have had previous disease. Among 364 subjects who could be formally tested, 112 had a 15-decibel or greater hearing loss in the speech frequencies. Among these Indians, middle-ear disease began early in life and recurrences were frequent. The prevalence of aural disease was related to poor social conditions, family history and presence of nasal discharge. No other relationships could be demonstrated, and there was no evident benefit from adenotonsillectomy. No secretory otitis or otosclerosis and almost no sensorineural high-tone hearing loss were discovered.     

Effectiveness of adenotonsillectomy in children with mild symptoms of throat infections or adenotonsillar hypertrophy: open,randomised controlled trial

Objective To assess the effectiveness of adenotonsillectomy in children with mild symptoms of throat infections or adenotonsillar hypertrophy.Design Open, randomised controlled trial.Setting 21 general hospitals and three academic centres in the Netherlands.Participants 300 children aged 2-8 years requiring adenotonsillectomy.Intervention Adenotonsillectomy compared with watchful waiting.Main outcome measures Episodes of fever, throat infections, upper respiratory tract infections, and health related quality of life.Results During the median follow up period of 22 months, children in the adenotonsillectomy group had 2.97 episodes of fever per person year compared with 3.18 in the watchful waiting group (difference -0.21, 95% confidence interval -0.54 to 0.12), 0.56 throat infections per person year compared with 0.77 (-0.21, -0.36 to -0.06), and 5.47 upper respiratory tract infections per person year compared with 6.00 (-0.53, -0.97 to -0.08). No clinically relevant differences were found for health related quality of life. Adenotonsillectomy was more effective in children with a history of three to six throat infections than in those with none to two. 12 children had complications related to surgery.Conclusion Adenotonsillectomy has no major clinical benefits over watchful waiting in children with mild symptoms of throat infections or adenotonsillar hypertrophy.