Serotonin reduction in post-acute sequelae of viral infection.

Post-acute sequelae of COVID-19 (PASC, "Long COVID") pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction. Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes.

A wide range of protective and predisposing variants in aggrecan influence the susceptibility for otosclerosis.

In this study, we investigated the association of ACAN variants with otosclerosis, a frequent cause of hearing loss among young adults. We sequenced the coding, 5'-UTR and 3'-UTR regions of ACAN in 1497 unrelated otosclerosis cases and 1437 matched controls from six different subpopulations. The association between variants in ACAN and the disease risk was tested through single variant and gene-based association tests. After correction for multiple testing, 14 variants were significantly associated with otosclerosis, ten of which represented independent association signals. Eight variants showed a consistent association across all subpopulations. Allelic odds ratios of the variants identified four predisposing and ten protective variants. Gene-based tests showed an association of very rare variants in the 3'-UTR with the phenotype. The associated exonic variants are all located in the CS domain of ACAN and include both protective and predisposing variants with a broad spectrum of effect sizes and population frequencies. This includes variants with strong effect size and low frequency, typical for monogenic diseases, to low effect size variants with high frequency, characteristic for common complex traits. This single-gene allelic spectrum with both protective and predisposing alleles is unique in the field of complex diseases. In conclusion, these findings are a significant advancement to the understanding of the etiology of otosclerosis.

Variants affecting diverse domains of MEPE are associated with two distinct bone disorders, a craniofacial bone defect and otosclerosis.

PURPOSE: To characterize new molecular factors implicated in a hereditary congenital facial paresis (HCFP) family and otosclerosis. METHODS: We performed exome sequencing in a four-generation family presenting nonprogressive HCFP and mixed hearing loss (HL). MEPE was analyzed using either Sanger sequencing or molecular inversion probes combined with massive parallel sequencing in 89 otosclerosis families, 1604 unrelated affected subjects, and 1538 unscreened controls. RESULTS: Exome sequencing in the HCFP family led to the identification of a rare segregating heterozygous frameshift variant p.(Gln425Lysfs*38) in MEPE. As the HL phenotype in this family resembled otosclerosis, we performed variant burden and variance components analyses in a large otosclerosis cohort and demonstrated that nonsense and frameshift MEPE variants were significantly enriched in affected subjects (p = 0.0006-0.0060). CONCLUSION: MEPE exerts its function in bone homeostasis by two domains, an RGD and an acidic serine aspartate-rich MEPE-associated (ASARM) motif inhibiting respectively bone resorption and mineralization. All variants associated with otosclerosis are predicted to result in nonsense mediated decay or an ASARM-and-RGD-truncated MEPE. The HCFP variant is predicted to produce an ASARM-truncated MEPE with an intact RGD motif. This difference in effect on the protein corresponds with the presumed pathophysiology of both diseases, and provides a plausible molecular explanation for the distinct phenotypic outcome.

Star-shaped Polymers through Simple Wavelength-Selective Free-Radical Photopolymerization.

Star-shaped polymers represent highly desired materials in nanotechnology and life sciences, including biomedical applications (e.g., diagnostic imaging, tissue engineering, and targeted drug delivery). Herein, we report a straightforward synthesis of wavelength-selective multifunctional photoinitiators (PIs) that contain a bisacylphosphane oxide (BAPO) group and an α-hydroxy ketone moiety within one molecule. By using three different wavelengths, these photoactive groups can be selectively addressed and activated, thereby allowing the synthesis of ABC-type miktoarm star polymers through a simple, highly selective, and robust free-radical polymerization method. The photochemistry of these new initiators and the feasibility of this concept were investigated in unprecedented detail by using various spectroscopic techniques.

COL1A1 association and otosclerosis: a meta-analysis.

Otosclerosis is a disease of abnormal bone remodeling in the human otic capsule that can lead to progressive hearing loss. Little of the underlying disease etiology has been elucidated thus far, although several studies have suggested that COL1A1 may play a role based on its importance in bone metabolism and other diseases like osteoporosis and osteogenesis imperfecta. Genetic association studies between COL1A1 and otosclerosis, however, have been contradictory. To resolve this issue, we studied a large Belgian-Dutch and a Swiss population for a genetic association between COL1A1 and otosclerosis and additionally performed a meta-analysis to investigate the overall genetic effect of COL1A1 on all otosclerosis populations studied to date. We found a significant association both in the Belgian-Dutch population and in the meta-analysis. In aggregate, our analysis supports evidence for an association between COL1A1 and otosclerosis although effect sizes of the variants reported in the initial studies are likely to be an overestimate of true effect sizes.

Neuromuscular choristoma of the internal auditory meatus.

Choristomas of the internal auditory meatus are exceedingly rare tumors. In most cases, neuromuscular choristomas have initially been misdiagnosed as vestibular schwannomas (VS). No known characteristics in the clinical presentation or in imaging exist distinguishing these tumors from VS, which are the most common tumors at this location [Smith et al.: AJNR Am J Neuroradiol 1997;18:327-329]. We present a case of a neuromuscular choristoma of the 8th cranial nerve that was operated because of growth demonstrated on two MRI scans 3 months apart. We were convinced that this young patient would require treatment sometime in the future, and we believed that an operation at that time had higher chances to preserve the anatomical structures. Histomorphological examination of the tumor revealed a nodular lesion with fascicular and nodular assembled smooth muscle cells, connective tissue and nerve fibers.

Mucociliary Clearance Differs in Mild Asthma by Levels of Type 2 Inflammation.

BACKGROUND: Although mucus plugging is a well-reported feature of asthma, whether asthma and type 2 inflammation affect mucociliary clearance (MCC) is unknown. RESEARCH QUESTION: Does type 2 inflammation influence mucus clearance rates in patients with mild asthma who are not receiving corticosteroids? STUDY DESIGN AND METHODS: The clearance rates of inhaled radiolabeled particles were compared between patients with mild asthma with low (n = 17) and high (n = 18) levels of T2 inflammation. Fraction exhaled nitric oxide (Feno) was used to prospectively segregate subjects into T2 Lo (Feno < 25 ppb) and T2 Hi (Feno > 35 ppb) cohorts. Bronchial brush samples were collected with fiber-optic bronchoscopy, and quantitative polymerase chain reaction was performed to measure expression of genes associated with T2 asthma. MCC rate comparisons were also made with a historical group of healthy control subjects (HCs, n = 12). RESULTS: The T2 Lo cohort demonstrated increased MCC when compared with both T2 Hi and historic HCs. MCC within the T2 Hi group varied significantly, with some subjects having low or zero clearance. MCC decreased with increasing expression of several markers of T2 airway inflammation (CCL26, NOS2, and POSTN) and with Feno. MUC5AC and FOXJ1 expression was similar between the T2Lo and T2Hi cohorts. INTERPRETATION: Increasing T2 inflammation was associated with decreasing MCC. High rates of MCC in T2 Lo subjects may indicate a compensatory mechanism present in mild disease but lost with high levels of inflammation. Future studies are required to better understand mechanisms and whether impairments in MCC in more severe asthma drive worse clinical outcomes.

Antibodies from malaria-exposed Malians generally interact additively or synergistically with human vaccine-induced RH5 antibodies.

Reticulocyte-binding protein homolog 5 (RH5) is a leading Plasmodium falciparum blood-stage vaccine candidate. Another possible candidate, apical membrane antigen 1 (AMA1), was not efficacious in malaria-endemic populations, likely due to pre-existing antimalarial antibodies that interfered with the activity of vaccine-induced AMA1 antibodies, as judged by in vitro growth inhibition assay (GIA). To determine how pre-existing antibodies interact with vaccine-induced RH5 antibodies, we purify total and RH5-specific immunoglobulin Gs (IgGs) from malaria-exposed Malians and malaria-naive RH5 vaccinees. Infection-induced RH5 antibody titers are much lower than those induced by vaccination, and RH5-specific IgGs show differences in the binding site between the two populations. In GIA, Malian polyclonal IgGs show additive or synergistic interactions with RH5 human monoclonal antibodies and overall additive interactions with vaccine-induced polyclonal RH5 IgGs. These results suggest that pre-existing antibodies will interact favorably with vaccine-induced RH5 antibodies, in contrast to AMA1 antibodies. This study supports RH5 vaccine trials in malaria-endemic regions.

Genetic variants in the RELN gene are associated with otosclerosis in multiple European populations.

Otosclerosis is a common form of hearing loss characterized by abnormal bone remodeling in the otic capsule. It is considered a complex disease caused by both genetic and environmental factors. In a previous study, we identified a region on chr7q22.1 located in the RELN gene that is associated with otosclerosis in Belgian-Dutch and French populations. Evidence for allelic heterogeneity was found in this chromosomal region in the form of two independent signals. To confirm this finding, we have completed a replication study that includes four additional populations from Europe (1,141 total samples). Several SNPs in this region replicated in these populations separately. While the power to detect significant association in each population is small, when all four populations are combined, six of seven SNPs replicate and show an effect in the same direction as in the previous populations. We also confirmed the presence of allelic heterogeneity in this region. These data further implicate RELN in the pathogenesis of otosclerosis. Functional research is warranted to determine the pathways through which RELN acts in the pathogenesis of otosclerosis.

On the functional compartmentalization of the normal middle ear. Morpho-histological modelling parameters of its mucosa.

BACKGROUND: Middle ear physiology includes both sound pressure transmission and homeostasis of its static air pressure. Pressure gradients are continuously created by gas exchange over the middle ear mucosa as well as by ambient pressure variations. Gas exchange models require actual values for regional mucosa thickness, blood vessel density, and diffusion distance. Such quantitative data have been scarce and limited to few histological samples from the tympanic cavity (TC) and the antrum. However, a detailed regional description of the morphological differences of the TC and mastoid air cell system (MACS) mucosa has not been available. The aim of the present study was to provide such parameters. METHODS: The study included sets of three histological H&E-slides from 15 archived healthy temporal bones. We performed a comparison of the mucosa morphology among the following regions: (1) anterior TC; (2) inferior TC; (3) posterior TC; (4) superior TC; (5) MACS antrum; (6) superior MACS; (7) central MACS; (8) inferior MACS. RESULTS: Regions (1)-(3), situated below the inter-attico-tympanic diaphragm, had the largest proportion of high respiratory epithelium, cilia and loose lamina propria within the mucosa, as well as the thickest mucosa and the largest diffusion distance. Regions (6)-(8), situated above the diaphragm, had the thinnest mucosa, the shortest distance to the blood vessels, together with the largest proportion of flat epithelium and very few cilia. Regions (4)-(5), still supradiaphragmatic, had intermediary values for these parameters, but generally closer to regions (6)-(8). The blood vessel density and the proportion of active mucosa were not significantly different among the regions. CONCLUSION: Mucosa of regions (1), (2) and (3) represented a predominantly clearance-specific morphology, whereas in regions (4)-(8) it seemed adapted to gas exchange. However, the lack of statistically significant differences in blood vessel density and proportion of active mucosa indicated that all regions could be involved in gas exchange with the highest adaptation in the superior MACS. This pattern divides the middle ear functionally along the inter-attico-tympanic diaphragm rather than the anatomical division into TC and MACS.

Deposition studies of aerosol delivery by nasal cannula to infants.

AIM: Nasal cannulas are used to provide oxygen support for infants and have been considered as a means for delivering aerosols to the lungs. To measure mucociliary clearance in the lungs of infants with congenital heart defects, we delivered radiopharmaceutical aerosols via a nasal cannula. Here we report on the pulmonary and nasal deposition of these aerosols. METHOD: A total of 18 infants (median age = 26 days; quartiles = 11-74 days) performed clearance measurements soon before or after corrective cardiac surgery. The regional aerosol deposition was assessed using gamma camera imaging. RESULTS: Cannula flow rate significantly affected pulmonary dosing. Flow rates useful for oxygen support were associated with low pulmonary deposition (2 L/min; mean, 4.5% of deposited dose; range, 2%-9%; n = 7) and high nasal deposition. Much lower cannula flow rates increased the pulmonary deposition (0.2 L/min; mean, 33.5% of deposited dose; range, 15%-51%; n = 5; P = 0.005 vs 2 L/min). The ratio of nose/lung dosing was approximately 26:1 at 2 L/min and 2:1 at 0.2 L/min. Bench studies demonstrated cannula output rates of 10.2 ± 1.7% (2 L/min) and 3.3 ± 0.4% (0.2 L/min) of the loaded nebulizer dose during a 2-minute delivery. Combining in vitro and in vivo results, we estimate that 0.46% of the loaded nebulizer dose reaches the lungs at 2 L/min vs 1.10% at 0.2 L/min during a 2-minute delivery. CONCLUSION: With the delivery system used here, pulmonary aerosol delivery via nasal cannula was very inefficient at the flow rates required to provide oxygen support. Even at low flows, nasal deposition was substantial and local toxicity must be considered.

Multiprobe Nuclear Imaging of the Cystic Fibrosis Lung as a Biomarker of Therapeutic Effect.

Background: Nuclear imaging biomarkers illustrate unique aspects of lung physiology and are useful for assessing therapeutic effects in cystic fibrosis (CF) lung disease. We have developed a multiprobe method to simultaneously measure mucociliary clearance (MCC) and paracellular absorption (ABS). MCC is a direct measure of mucus clearance. ABS has been related to airway surface liquid (ASL) absorption through previous in vitro studies. Methods: We describe baseline factors affecting MCC and ABS using data from a retrospective baseline group (n = 22) and the response of the measures to inhaled 7% hypertonic saline (HS) and dry powder mannitol using data from a prospective response group (n = 7). A retrospective healthy control group (n = 15) is also described. The baseline and control groups performed single measurements of MCC/ABS. The response group performed baseline measurements of MCC/ABS and measurements after each intervention. Results: ABS was correlated (Spearman's ρ = 0.51, p = 0.06) to sweat chloride, a systemic measure of cystic fibrosis transmembrane conductance regulator (CFTR) function, whereas MCC was not. Baseline MCC was depressed after Pseudomonas aeruginosa infection as we have previously described. MCC provided a more sensitive indication of therapeutic effect and indicated improved clearance with mannitol compared with HS. Conclusion: MCC provides a useful and well-established means of testing therapies directed at improving mucus clearance in the lung. ABS may provide a means of detecting local changes in ASL absorption and CFTR function in the lung. Both are useful tools for studying the key aspects of CF lung pathophysiology (ASL hyperabsorption and MCC depression) that link the basic genetic defects of CF to disease manifestations in the lung.

Innovations in Doctoral Training and Research on Tinnitus: The European School on Interdisciplinary Tinnitus Research (ESIT) Perspective.

Tinnitus is a common medical condition which interfaces many different disciplines, yet it is not a priority for any individual discipline. A change in its scientific understanding and clinical management requires a shift toward multidisciplinary cooperation, not only in research but also in training. The European School for Interdisciplinary Tinnitus research (ESIT) brings together a unique multidisciplinary consortium of clinical practitioners, academic researchers, commercial partners, patient organizations, and public health experts to conduct innovative research and train the next generation of tinnitus researchers. ESIT supports fundamental science and clinical research projects in order to: (1) advancing new treatment solutions for tinnitus, (2) improving existing treatment paradigms, (3) developing innovative research methods, (4) performing genetic studies on, (5) collecting epidemiological data to create new knowledge about prevalence and risk factors, (6) establishing a pan-European data resource. All research projects involve inter-sectoral partnerships through practical training, quite unlike anything that can be offered by any single university alone. Likewise, the postgraduate training curriculum fosters a deep knowledge about tinnitus whilst nurturing transferable competencies in personal qualities and approaches needed to be an effective researcher, knowledge of the standards, requirements and professionalism to do research, and skills to work with others and to ensure the wider impact of research. ESIT is the seed for future generations of creative, entrepreneurial, and innovative researchers, trained to master the upcoming challenges in the tinnitus field, to implement sustained changes in prevention and clinical management of tinnitus, and to shape doctoral education in tinnitus for the future.

Functional Results and Subjective Benefit of a Transcutaneous Bone Conduction Device in Patients With Single-Sided Deafness.

OBJECTIVE: To analyze speech discrimination scores and subjective benefit of a transcutaneous bone conduction device (tBCD) in adults with single-sided deafness (SSD). STUDY DESIGN: Prospective cohort study. SETTING: Tertiary referral center. PATIENTS: Nine adults with SSD for more than 1 year and normal hearing on the contralateral side (PTA <30 dB HL) were implanted with a tBCD. INTERVENTIONS: Transmastoidal implantation of a Bonebridge (BB, MED-EL) tBCD. MAIN OUTCOME MEASURES: Aided and unaided speech discrimination scores in three different spatial settings were measured using the Oldenburg sentence test (OLSA). Quality of life was assessed by two questionnaires, the Bern Benefit in Single Sided Deafness Questionnaire (BBSS) and the Speech, Spatial and Qualities of Hearing scale for benefit questionnaire (SSQ-B). RESULTS: Speech discrimination scores measured by OLSA showed a mean signal-to-noise ratio improvement of 1.7 dB SPL for the aided condition compared with the unaided condition in the setting where the sound signal is presented on the side of the implanted ear and the noise is coming from the front (p < 0.05). In the other two settings (signal and noise from front; signal from normal hearing ear and noise from front), the signal-to-noise ratio did not change significantly. This benefit became manifest after 6 months. Good satisfaction was indicated by positive results on the questionnaires. CONCLUSION: Speech discrimination in noise for patients implanted with the BB is comparable with patients with other bone conduction hearing aids. A learning curve is clearly detectable. The subjective benefit was rated positively by the patients. With the advantage of intact skin conditions after implantation, the BB is an adequate option for patients with SSD.

The incudo-malleolar joint and sound transmission losses.

The question as to whether the incudo-malleolar joint (IMJ) is mobile or immobile at moderate sound pressure levels (SPLs) is addressed. Referring to the mechanical properties of elastic tissue, we suggest that the IMJ is mobile at any SPL. In order to test this hypothesis, we investigated the dynamics of the IMJ in nine temporal bones by means of laser scanning doppler vibrometry. The dynamic behavior of both ossicles, malleus and incus is described by three degrees of freedom, and transfer functions (TFs) are shown for each motion component [corrected]. We show that there is indeed relative motion between the malleus and the incus. This transmission loss affects the middle ear TF and results in a frequency dependent sound transmission loss. Some characteristics of our results are in agreement with middle ear TFs described in the literature. The increasing transmission loss towards higher frequencies is caused by relative motion between malleus and incus at the IMJ. The concept that the IMJ is functionally mobile is consistent with the physical properties of elastic tissues which most likely define the mechanics of this joint. Since the IMJ is indeed mobile at moderate sound intensities and audible frequencies the theory of the lever ratio being responsible for the characteristics of the middle ear TF must be reconsidered.

Round window atresia and its effect on sound transmission.

OBJECTIVE: To document isolated round window atresia and to discuss its impact on current theories of inner ear function. PATIENTS AND STUDY DESIGN: Retrospective analysis of isolated round window atresia suggesting an autosomal dominant inheritance pattern and review of current concepts of cochlear macromechanics. SETTING: Tertiary referral center. RESULTS: The unexpected finding of isolated round window atresia in two female patients of the same family was confirmed intraoperatively as well as postoperatively using high-resolution computed tomography. The current audiograms and the review of the literature highlight a mixed, but predominantly conductive, hearing impairment with thresholds at 30 to 40 dB. Implying that there is no pressure release mechanism for inner ear fluid displaced by the stapes footplate, a total conductive hearing loss would be expected. CONCLUSIONS: The rare finding of round window atresia can be overlooked at surgery because of insufficient exposure of the round window niche. High-resolution computed tomography confirms the round window obliteration. It seems that an alternative way of cochlear stimulation takes place besides the concept of fluid bulk shifting. Surgery seems not to guarantee favorable results.

How does closure of tympanic membrane perforations affect hearing and middle ear mechanics? An evaluation in a patient cohort and temporal bone models.

OBJECTIVE: This study aimed to determine how tympanic membrane (TM) perforations and their closure, using a paper-patch technique, affect middle-ear mechanics and, thus, conductive hearing for different sizes of the TM perforation. STUDY DESIGN: Temporal bone (TB) study and prospective clinical trial. SETTING: Tertiary referral center. PATIENTS: Nine patients with chronic otitis media for more than 3 months. INTERVENTION: The TM perforations were closed with a paper patch in all 9 patients. In 5 of 9 patients, myringoplasty was performed. Matching TM perforations were created in a TB model (n = 8) and closed using the paper patch. MAIN OUTCOME MEASURES: Air-bone gap was measured in all 9 patients of the patient cohort with TM perforations before and after closure and in 5 patients after myringoplasty. Stapes velocity and sound pressure difference between the ear canal and middle-ear cavity were measured in TBs with intact TM, with TM perforations, and with the perforations closed by the paper patch. All measurements in the patient cohort and TBs were performed for different sizes of TM perforations to determine if the effects varied as a function of size. RESULTS: Degree of the air-bone gap differed as a function of size of the TM perforations and its recovery after closure, and myringoplasty was independent of the size of the TM perforation in the frequency range of 0.25 to 4 kHz. In the TB measurements, although pressure difference across the TM was almost fully recovered by closing the perforation with a paper patch, recovery of the stapes motion was limited at frequencies above 4.5 kHz for larger sizes of TM perforations. CONCLUSION: Hearing loss caused by TM perforations depends on the size of the perforation. Hearing returns almost completely across the frequency range after closure except above 4 kHz for larger perforations. This is because the structural damage caused by large TM perforations cannot be completely restored by application of a paper patch.

Biocompatibility of nitinol stapes prosthesis.

OBJECTIVE: Use of the SMart piston, a nitinol-based, self-crimping prosthesis in stapes surgery may allow improved functional results because of better sound transmission properties at the incus-prosthesis interface because of the elimination of manual crimping. Possible disadvantages include thermal damage or strangulation of the incus and its mucoperiosteum or nickel intolerance. The goal of this study was to morphologically assess the fixation of this prosthesis to the incus, investigate the reaction of the middle ear mucosa to the prosthesis, identify alterations to the incudal bone, and detect deposits of nickel in the tissue around the prosthesis. STUDY DESIGN: Prospective consecutive case analysis. SETTING: Tertiary referral center. PATIENTS: Four patients with an unfavorable functional result after primary SMart-piston stapedotomy. INTERVENTION: Revision malleostapedotomy with explantation of the incus and prosthesis for further analysis. MAIN OUTCOME MEASURES: Analysis of intraoperative findings and postoperative examination of the explants using light- and scanning-electron microscopy, energy dispersive x-ray analysis, and atom absorption spectrometry. RESULTS: The intraoperative, macroscopic, and scanning electron microscopic investigation showed tight circular fixation of the prostheses, whereas a gap between the prosthesis and the lateral incus was found in 1 case. All prostheses were overgrown by mucosa. Superficial localized erosion of the incudal bone was found in 2 cases. There was no elevation in nickel content in the removed tissue samples. CONCLUSION: The lateral gap between prosthesis and incus did not affect fixation of the prosthesis, neither did covering by a mucosal layer. Bone erosion was most likely caused by laser in one and by the prosthesis in another explant. No signs of increased nickel deposits could be found on energy dispersive x-ray analysis or atom absorption spectrometry. We conclude that a nitinol stapes prosthesis is safe for treatment of stapedial fixation.

The impact of platelet-derived growth factor on closure of chronic tympanic membrane perforations: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: Patients with tympanic membrane (TM) perforations often have infections, and repetitive topical treatment may be required. These infections can be prevented by permanent closure of the TM perforation. Different surgical treatment options have been described, but noninvasive techniques may be preferred as they carry less risk than surgery. One noninvasive approach is to induce wound healing by application of growth factors. The effect and clinical use of applying topical platelet-derived growth factor (PDGF) for decrease of size and closure of chronic TM perforations is evaluated. STUDY DESIGN: Prospective, randomized, placebo-controlled, double-blind study. SETTING: Tertiary referral center. PATIENTS: Twenty patients with chronic suppurative otitis media without cholesteatoma for more than 3 months. INTERVENTION: Topical treatment with PDGF or placebo applied weekly to the TM for 6 weeks. MAIN OUTCOME MEASURES: Success rate, defined as a reduction of perforation size of 50% or more to determine relative changes of the perforation size; effect of initial size and location of TM perforation on success rate; and air and bone conduction thresholds to determine air-bone gap measured before treatment. RESULTS: Randomization made matching pretreatment perforation size of the 2 study groups impossible, and the initial rate perforation/TM was significantly smaller in the PDGF group. No difference between the 2 groups was found for perforation/TM less than 10%. However, success rate did not differ significantly between the 2 groups (power = 0.8), and the effect of PDGF was found to be small (-2%; standard deviation, ±49%). Initial size and position of the TM perforation were not significant factors determining success. Mean air-bone gap for the frequencies of 0.5, 1, 2, and 4 kHz was 22.5 dB. CONCLUSION: The topical application of PDGF as an office treatment for chronic otitis media is not a favorable alternative to surgery.