Safety, tolerability, and effect of a single aural dose of Dornase alfa at the time of ventilation tube surgery for otitis media: A Phase 1b double randomized control trial.

BACKGROUND: One third of children require repeat ventilation tube insertion (VTI) for otitis media. Disease recurrence is associated with persistent middle ear bacterial biofilms. With demonstration that Dornase alfa (a DNase) disrupts middle ear effusion biofilms ex vivo, we identified potential for this as an anti-biofilm therapy to prevent repeat VTI. First, safety and tolerability needed to be measured. METHODS: This was a phase 1B double-blinded randomized control trial conducted in Western Australia. Children between 6 months and 5 years undergoing VTI for bilateral middle ear effusion were recruited between 2012 and 2014 and followed for two years. Children's ears were randomized to receive either Dornase alfa (1 mg/mL) or 0.9 % sodium chloride (placebo) at time of surgery. Children were followed up at 2 weeks post-VTI and at 3-monthly intervals for 2 years. Outcomes assessed were: 1) safety and tolerability, 2) otorrhoea frequency, 3) blocked or extruded ventilation tube (VT) frequency, 4) time to blockage or extrusion, 5) time to infection recurrence and/or need for repeat VTI. RESULTS: Sixty children (mean age 2.3 years) were enrolled with 87 % reaching study endpoint. Treatment did not change otorrhoea frequency. Hearing improved in all children following VTI, with no indication of ototoxicity. Dornase alfa had some effect on increasing time until VT extrusion (p = 0.099); and blockage and/or extrusion (p = 0.122). Frequency of recurrence and time until recurrence were similar. Fourteen children required repeat VTI within the follow-up period. CONCLUSION: A single application of Dornase alfa into the middle ear at time of VTI was safe, non-ototoxic, and well-tolerated. TRIAL REGISTRATION: ACTRN12623000504617.

Experience is more important than technology in paediatric post-tonsillectomy bleeding.

BACKGROUND: Paediatric tonsillectomy is a common procedure and one of the first skills acquired by surgical trainees. Post-tonsillectomy bleeding is one of the most significant complications. This study examined post-tonsillectomy bleed rates associated with technology and level of surgical experience. METHODS: Data were collected on all tonsillectomies performed by surgical consultants (n = 6) and trainees (n = 10) at affiliated hospitals over a nine-month period. Hospital records were audited for post-tonsillectomy bleeding re-admissions and returns to the operating theatre. RESULTS: A total of 1396 tonsillectomies were performed (279 by trainees, 1117 by consultant surgeons). Primary post-tonsillectomy bleed rates were equivalent between trainees and consultants. Secondary bleed rates were significantly greater for trainees (10.0 per cent) compared to consultants (3.3 per cent), as were return to operating theatre rates (2.5 per cent vs 0.7 per cent). Amongst consultants, technology used was not associated with differences in secondary post-tonsillectomy bleeding and returns to the operating theatre. CONCLUSION: Our data suggest that experience of the surgeon may have greater bearing on post-tonsillectomy bleed rates than the technology used.

Congenital nasal pyriform aperture stenosis 5.7 mm or less is associated with surgical intervention: A pooled case series.

OBJECTIVES: Congenital nasal pyriform aperture stenosis (CNPAS) is a rare cause of upper airway obstruction in the newborn. CNPAS is diagnosed clinically and confirmed with CT scanning. Early diagnosis and management is essential for this potentially life-threatening condition. Patients can be managed conservatively or surgically. Surgical treatment is usually reserved for those patients that fail conservative treatment. Our objective was to provide a radiologically-measured pyriform aperture (PA) width that predicts the need for surgical intervention. METHODS: This study was a retrospective chart review of patients treated in a tertiary paediatric hospital as well as a review of the literature. Outcome measures were defined as surgical or conservative intervention for the management of congenital pyriform aperture stenosis. RESULTS: Data from 26 individual patients (7 patients from our own case series and 19 patients from previously published reports) was analysed to calculate those patients requiring surgical intervention. CONCLUSIONS: A PA width of less than 5.7 mm in a neonate is 88% sensitive and specific in predicting that a patient will require surgical intervention.

Novel use of Coblation technology in an unusual congenital tracheal stenosis.

BACKGROUND: We report the case of an unusual late presentation of congenital tracheal stenosis in a 13-year-old boy. He was treated with minimally invasive Coblation resection of the stenotic segment, avoiding a major open tracheal resection and reconstruction. This case report is the first to document the use of an ultra-fine Coblation wand in the treatment of congenital tracheal stenosis. RESULTS: The case proceeded well, without any complications. The patient had a fully healed and patent trachea at 12-week post-operative review. CONCLUSION: Complex cases of congenital stenosis should be managed with a multidisciplinary approach. Different and novel treatment options should be explored to find one that suits the individual patient. Minimally invasive Coblation technology can offer less invasive treatment with quicker recovery and shorter hospitalisation.

A review of the burden of disease due to otitis media in the Asia-Pacific.

OBJECTIVE: The burden of disease due to otitis media (OM) in Asia Pacific countries was reviewed to increase awareness and raise understanding within the region. METHODS: Published literature and unpublished studies were reviewed. RESULTS: In school-age children, OM prevalence varied between 3.25% (Thailand) and 12.23% (Philippines) being highest (42%) in Aboriginal Australian children. OME prevalence at school age varied between 1.14% (Thailand) and 13.8% (Malaysia). Higher prevalence was reported in children with hearing impairment, HIV, pneumonia and rhinitis. CSOM prevalence was 5.4% in Indonesia (all ages), 15% in Aboriginal Australian children and 2-4% in Thailand, Philippines, Malaysia and Vietnam (WHO estimate). OM prevalence/incidence and service utilisation were highest in children 2-5 years of age. The disease burden was substantially higher in Pacific Island children living in New Zealand (25.4% with OME), and was highest in indigenous Australians (>90% with any OM). Streptococcus pneumoniae and Haemophilus influenzae dominated as primary causes of AOM in all studies. Few studies examined pneumococcal serotype distribution. Health-related cost estimates for OM, when available, were substantial. In developing countries, significant investment is needed to provide facilities for detection and treatment of ear disease in children, if long term hearing deficits and other sequelae are to be prevented. CONCLUSION: The available evidence suggests an important burden of disease and economic cost associated with OM in most Asia Pacific countries and a potential benefit of prevention through vaccination. Large, prospective community-based studies are needed to better define the prevalence of ear disease in children, and to predict and track pneumococcal conjugate vaccine impacts. AOM prevention through vaccination may also provide a means of reducing antibiotic use and controlling antibiotic-resistant disease in children. This review highlights the need for additional research, and provides a basis on which to build and develop regional guidelines for OM management.

FBXO11, a regulator of the TGFß pathway, is associated with severe otitis media in Western Australian children.

Otitis media (OM) is a common childhood disease characterised by middle ear inflammation following infection. Susceptibility to recurrent acute OM (rAOM) and chronic OM with effusion (COME) is highly heritable. Two murine mutants, Junbo and Jeff, spontaneously develop severe OM with similar phenotypes to human disease. Fine-mapping of these mutants identified two genes (Evi1 and Fbxo11) that interact with the transforming growth factor ß (TGFß) signalling pathway. We investigated these genes, as well as four Sma- and Mad-related (SMAD) genes of the TGFß pathway, as candidate rAOM/COME susceptibility genes in two predominantly Caucasian populations. Single-nucleotide polymorphisms (SNPs) within FBXO11 (family-based association testing Z-Score=2.61; P(best)=0.009) were associated with severe OM in family-based analysis of 434 families (561 affected individuals) from the Western Australian Family Study of OM. The FBXO11 association was replicated by directed analysis of Illumina 660W-Quad Beadchip data available for 253 cases and 866 controls (OR=1.55 (95% CI 1.28-1.89); P(best)=6.9 × 10(-6)) available within the Western Australian Pregnancy Cohort (Raine) Study. Combined primary and replication results show P(combined)=2.98 × 10(-6). Neither cohort showed an association with EVI1 variants. Family-based associations at SMAD2 (P=0.038) and SMAD4 (P=0.048) were not replicated. Together, these data provide strong evidence for FBXO11 as a susceptibility gene for severe OM.

When is the vestibular aqueduct enlarged? A statistical analysis of the normative distribution of vestibular aqueduct size.

BACKGROUND AND PURPOSE: The size of vestibular aqueducts (VAs) seen on CT studies varies. The current practice of calling a VA enlarged when it exceeds a certain threshold (eg, 1.5 mm at the midpoint) is arbitrary. Our hypothesis was that statistical analysis of the range of VA widths in a normal-hearing population would lead to a mathematic definition of the upper-limit-of-normal VA width. MATERIALS AND METHODS: The VA midpoint and opercular widths were measured in 73 children with normal hearing. Statistical analysis yielded values of the 99 th, 97.5th, 95th, 90th, 75th, and 50th percentiles for this normal distribution. RESULTS: The upper-limit-of-normal (95th percentile) values for the VA midpoint and opercular widths were 0.9 and 1.9 mm, respectively. The VAs with greater widths may reasonably be considered enlarged. CONCLUSION: The VAs with midpoint or opercular widths of 1.0 and 2.0 mm or greater, respectively, are enlarged.

Histology of AlphaCor skirts: evaluation of biointegration.

PURPOSE: To report histologic findings in 14 AlphaCor artificial corneas implanted during clinical trials and subsequently explanted from human subjects following complications, so as to evaluate biointegration within the device skirt. METHODS: Explants were fixed and sectioned in paraffin. Histologic findings related to the device skirt were compared with earlier histologic results from animal studies and correlated with clinical histories. RESULTS: Two devices had been removed due to complications related to the optic alone, 11 following stromal melting overlying the biointegratable sponge skirt and 1 due to a retroprosthetic membrane. All devices demonstrated normal skirt porosity. Biointegration was similar to that found in animal studies but qualitatively appeared reduced in the affected areas in patients with overlying stromal melting prior to explantation. Patients with a longer history of melting prior to explantation demonstrated presence of inflammatory cells around the device. CONCLUSIONS: Histologic findings of the AlphaCor skirt in humans are consistent with earlier animal studies. This study confirms that biointegration by host fibroblastic cells, with collagen deposition occurs after AlphaCor implantation in humans. In cases in which stromal melting had occurred, biointegration is seen to be reduced. On correlating preoperative clinical factors with biointegration observed histologically, preoperative vascularization appears not to be required for AlphaCor biointegration.

Retinal toxicity of intravitreal tenecteplase in the rabbit.

AIM: To investigate the retinal toxicity of intravitreal injection of a novel fibrinolytic tenecteplase in rabbit eyes. METHODS: Tenecteplase (25-350 micro g in 0.1 ml BSS) was injected into the vitreous cavity of normal rabbit eyes. Control (fellow) eyes received 0.1 ml of BSS. One day, 1 week, and 2 months post-injection, the eyes were examined by slit lamp biomicroscopy, indirect ophthalmoscopy, and electroretinography, and then harvested for histopathological examination. RESULTS: No evidence of retinal toxicity was seen with tenecteplase doses up to and including 50 micro g. At a dose of 150 micro g ophthalmoscopy was normal, but histology showed mild retinal damage in the inner nuclear layer and electroretinography showed a temporary reduction in B-wave amplitude. At doses of 200 micro g and above, there was evidence of retinal toxicity on electroretinography, ophthalmoscopy, and histology. Ophthalmoscopic findings included vitreal fibrosis, retinal necrosis and tractional retinal detachment and light microscopy revealed necrosis of retinal pigment epithelium and other retinal layers. Damage was centred around the injection site but was more widespread with the higher doses. CONCLUSION: A dose of 50 micro g tenecteplase appears safe for intravitreal injection in the rabbit. Tenecteplase could have potential applications in the treatment of submacular haemorrhage and retinal vein occlusion.

Is it necessary to screen for hearing loss in the paediatric population with osteogenesis imperfecta?

The aim of the study was to assess the necessity of a screening service to detect early hearing loss in the paediatric population with osteogenesis imperfecta. Twenty-two children were assessed over a 5-year period. Five children (22.7%) had normal hearing. Fourteen (63.6%) had conductive hearing loss, with 12 children in this group having otitis media with effusion (OME); all had resolution of hearing loss with appropriate therapy. Two children had persistent conductive losses unrelated to OME. Three children (13.6%) had sensorineural hearing loss, with one being detected at the age of 1 year. Existing evidence suggests that hearing loss associated with osteogenesis imperfecta has its onset in the second to third decade of life. Contrary to this, hearing loss was detected in 77.3% (17) of this population with a median and mean age of 9 years. This study would suggest that routine screening is worthwhile in children with osteogenesis imperfecta.

Feasibility of continuous transthoracic cardiac imaging using a novel ultrasound transducer.

BACKGROUND: The feasibility of hands-free transthoracic continuous ultrasonic cardiac imaging has not been demonstrated previously. We developed a 2.5-MHZ spherical transducer mounted in an external housing to permit steering in 360 degrees (CONTISON). The external housing was attached to the chest wall using an adhesive patch. METHODS AND RESULTS: The transducer was placed in the third or fourth interspace at the left sternal border to permit imaging of the left ventricle (LV) in its short axis and attached to the chest wall. The transducer then was attached to an ultrasound machine. Ten normal subjects and 20 patients with previous myocardial infarction were studied. The following maneuvers were performed at the beginning of the study: (1) The patient was rotated from the supine position (0 degrees ) in 20 degrees increments to the left lateral decubitus position (90 degrees ). The echocardiogram was displayed continuously and was recorded on videotape (parasternal short-axis view) at 0 degrees, 20 degrees, 40 degrees, 60 degrees, 80 degrees, and 90 degrees. (2) The patient was returned to the supine position and an echocardiogram was obtained. The patient was then seated up 20 degrees, 40 degrees, 60 degrees, 80 degrees, and 90 degrees by using the controls on the bed. (3) The patient then was returned to the supine position and the echocardiogram was displayed continuously on the monitor. The echocardiogram was recorded every 15 minutes for a period of 4 hours. All segments of the LV were visualized in the supine position and during lateral rotation (0 degrees -90 degrees ). Thus, body position did not affect the image. All segments of the LV were visualized during sitting up (0 degrees -90 degrees ), and all segments were visualized during the 4 hours of imaging. The patients were able to move around without distortion of the image. CONCLUSION: The CONTISON transducer permitted continuous imaging of LV wall motion. Body position did not affect interpretation of wall motion. This device has potential applicability in monitoring LV function in the intensive care setting.

Calcification of poly(2-hydroxyethyl methacrylate) hydrogel sponges implanted in the rabbit cornea: a 3-month study.

Poly(2-hydroxyethyl methacrylate) (PHEMA) hydrogels have been used in the past as ocular implants. In a recent development, PHEMA sponges have shown suitable properties as materials for the peripheral component of an artificial cornea (keratoprosthesis). However, the propensity of PHEMA to calcify could threaten the long-term stability of the implanted devices. In an attempt to improve the understanding of the calcification mechanism, the dynamics, extent, and nature of calcified deposits within PHEMA sponges implanted in the cornea were investigated in this study, and the possible correlation between necrosis of cells and calcification was critically examined. Samples of a PHEMA sponge were implanted in rabbit corneas and explanted at predetermined time points (2, 4, and 12 weeks). The samples were examined by microscopy (light, transmission, scanning) and energy dispersive analysis of X-rays. Histological assessment and semiquantitative analysis of the amount of calcium deposited was performed using image analysis. An in vitro experiment was also performed by incubating sponge samples for 2 weeks in a solution of calcium and phosphate ions at a ratio similar to that in hydroxyapatite, in the absence of cells. Calcification was not seen in the 2- and 4-week explants, however, small deposits were detected in two of the 12-week explants, both within and on the sponge's constituent polymer particles. The deposit volumes represented 0.094% and 0.21%, respectively, of the total sponge volumes. Calcium deposits were present in large amounts both within the constituent polymer particles and on the surface of the sponges incubated in the abiotic calcifying solution. Cooperative mechanisms are suggested for the calcification of PHEMA sponges in vivo. The initial event may occur at a molecular level, when plasma proteins are adsorbed onto the polymer surface and bound through chelation to the calcium ions present in the medium. After their natural degradation, these structures may act as nucleation sites for calcium phosphate crystallization. Concurrently, the calcium ions can diffuse into the hydrogel particles and then the spontaneous precipitation of calcium phosphate may be caused by supersaturation due to the lower content of water in polymer, an effect which is likely predominant in vitro. The second event is the recruitment of phagocytic cells to clear calcium debris. Degeneration of these cells may then form nucleation sites for secondary calcification.

Development and clinical assessment of an artificial cornea.

Keratoprosthesis research has been a gradual, rather fragmentary process with advances being made by isolated groups of researchers. This has arisen partly because of poor funding in the area; research groups which have achieved commercial support have often had constraints upon the full disclosure of their findings. Despite these difficulties there has been real progress over the last decade by several independent groups. This article concentrates upon our own development of a hydrogel core-and-skirt keratoprosthesis, the Chirila KPro, in order to illustrate the scientific and clinical problems common to keratoprosthesis research. Pilot data from a clinical trial is presented and the priorities for future research are discussed.

Development of a poly(2-hydroxyethyl methacrylate) orbital implant allowing direct muscle attachment and tissue ingrowth.

PURPOSE: To develop a poly(2-hydroxyethyl methacrylate) orbital implant that allows tissue ingrowth and direct muscle attachment to minimize the risk of extrusion and to enhance cosmesis. METHODS: Assessment of clinical outcomes and histologic findings after implantation of 18 prototype prostheses into rabbits. The implants were not wrapped with other tissues or materials. RESULTS: One case of infection was observed but there were no extrusions, with up to 21 months follow-up. Biocolonization was confirmed histologically. Good movement was observed when a cosmetic shell was fitted. CONCLUSIONS: The prototype prosthesis appears promising, with particular advantages being the direct attachment of extraocular muscles, good cosmesis and movement, and a low complication rate in this pilot study.

Synthesis, physical characterization, and biological performance of sequential homointerpenetrating polymer network sponges based on poly(2-hydroxyethyl methacrylate).

A limitation in the use of hydrophilic poly(2-hydroxyethyl methacrylate) (PHEMA) sponges as implantable devices is their inherently poor mechanical strength. This precludes proper surgical manipulation, especially in the eye where the size of the implant is usually small. In this study a new method was developed to produce mechanically stronger PHEMA sponges. Sequential homointerpenetrating polymer network (homo-IPN) sponges were made by using HEMA as the precursor for generating both the first network and the successive interpenetrated networks. Following the formation of network I, the sponge was squeezed to remove the interstitial water, soaked in the second monomer (also HEMA), and squeezed again to remove the excess monomer from the pores before being subjected to the second polymerization leading to the formation of network II. Two two-component IPN sponges (K2 and K4) with increasing HEMA content in the network II and a three-component IPN sponge (K3) were produced, and their properties were compared to those of a homopolymer PHEMA sponge (control). Apart from elongation, the tensile properties were all significantly enhanced in the IPN sponges; the water content was the same as in the control sponge, except for sponge K4, which was lower. Light microscopy revealed similar pore morphologies of the control and IPN sponges K2 and K3, and the majority of the pores were around 25 microm. Sponge K4 displayed smaller pores of around 10 microm. Cellular invasion into the sponges was examined in vitro (incubation with 3T3 fibroblasts) and in vivo (implantation in rabbit corneas). Although the in vitro assay detected a change in the cell behavior in the early stage of invasion, which was probably due to the formation of IPNs, such changes were not reflected in the longer term in vivo experiment. There was a proper integration of sponges K2 and K3 with the corneal stroma, but much less cellular invasion and no neovascularization in sponge K4. We concluded that IPN formation is a valid method to enhance the strength of PHEMA sponges, provided that the content of HEMA in the successive networks is not too high.

Correlation of histological findings with gadolinium enhanced MRI scans during healing of a PHEMA orbital implant in rabbits.

BACKGROUND/AIMS: To investigate a poly(2-hydroxyethyl methacrylate) (PHEMA) orbital implant with a spongy anterior hemisphere and a smooth gel posterior hemisphere, by histology correlated with magnetic resonance images. METHODS: Following enucleation, eight rabbits received PHEMA implants to which the muscles were directly sutured, and underwent gadolinium enhanced magnetic resonance imaging (MRI) from 3 to 52 weeks. After the rabbits were killed, the implants were removed, cut in a plane corresponding to the scan, and processed for light and electron microscopy. RESULTS: All eight rabbits retained their implant to the end of the study period without complications. The scans demonstrated muscle attachment to the anterior half of the implant, and enhancement was seen on injection of gadolinium chelate. Histology confirmed muscle attachment, and cellular and vascular ingrowth. Over time, a transformation from reactive inflammatory to relatively non-vascular scar tissue was seen within the implant. Calcium deposits in one implant were detected by imaging and histology. CONCLUSION: The implants are readily visualised on MRI. Muscle attachment and fibrovascular ingrowth into the anterior hemisphere are seen, while encapsulation of the posterior hemisphere is minimal. Histological findings confirm the progress of the healing response, with initial inflammation and marked vascularisation, developing later into quiescent scar tissue predominantly of fibroblasts.

Chorioretinal venous anastomoses: effect of different laser methods and energy in human eyes without vein occlusion.

BACKGROUND: This study was performed to determine the laser energy required to rupture both Bruch's membrane and retinal veins reliably in order to create a venous chorioretinal anastomosis. METHODS: A histological examination was conducted of argon green and YAG laser applications to the retina made prior to enucleation in eight eyes with large intraocular melanomas. RESULTS: Argon laser application of 50 microns in size and 0.1 s duration to intervascular areas of the retina will reliably rupture Bruch's membrane at a power level of at least 1.5 W. If the argon laser spot is placed overlying a retinal vein, a power level of up to 2.5-3.0 W will rupture Bruch's membrane in 60%, with only 34% of the retinal veins showing evidence of rupture. The YAG laser with power levels of 3-4 mJ will reliably rupture the retinal vein in cases where it has not previously been ruptured by the argon laser. CONCLUSION: When attempting to create a chorioretinal venous anastomosis in an eye with a non-ischaemic central retinal vein occlusion, Bruch's membrane should be ruptured first by placing the argon laser application at the side of the retinal vein before an attempt to rupture the retinal vein itself is made in case haemorrhage from the ruptured vein obscures the view. A power level of at least 2.5 W should be used. If the argon laser is unsuccessful in rupturing the retinal vein, a YAG laser (3-4 mJ) is effective.

Implantation of PHEMA keratoprostheses after alkali burns in rabbit eyes.

PURPOSE: We have previously examined histologically the healing of a PHEMA core-and-skirt keratoprosthesis (the Chirila KPro) as a full-thickness implant in healthy animal corneas. The present study was carried out to determine whether a diseased cornea could also generate biocolonization of the skirt region of a KPro. METHODS: Ten KPros were placed as full-thickness corneal implants under conjunctival flaps in 10 alkali-burned rabbit corneas. Histological findings at intervals from 2 weeks to 6 months postoperatively were compared with earlier findings in 10 rabbits that had received identical KPros without prior alkali injury. RESULTS: Despite severe corneal injury and the reduced keratocyte population present, there were no clinically detected complications in 60%. Histological findings established that, compared with healthy host tissue, skirt biocolonization and KPro-cornea healing after an alkali burn were impaired, with evidence of epithelial downgrowth in 40%. One animal required euthanasia earlier than the planned end point, but no KPro extrusions occurred. CONCLUSION: Biocolonization of a KPro skirt is reduced but not prevented in an alkali-induced corneal inflammation model. Although no extrusions occurred, close follow-up and anticollagenolytic medication would be required to minimize the complication rate.