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.

Understanding STEM academics' responses and resilience to educational reform of academic roles in higher education.

BACKGROUND: Across the globe, there have been significant reforms to improve STEM education at all levels. A significant part of this has been teacher reform. While the responses and resilience of STEM teachers to educational reforms in secondary education have received significant attention, the responses and resilience of STEM teachers in higher education remains understudied. In higher education, educational reforms of academic roles have seen increasing numbers of STEM academics focussed on education. Responses of STEM academics to education reform of the academic role have some parallels with teacher resilience, but there are also potential misalignments within a culture which values and prioritises science disciplinary research. This study examined the responses of STEM academics in higher education to educational reform of the academic role using the theoretical construct of resilience and Bronfenbrenner's socio-ecological model. This was a 2-year case study of 32 academics and senior educational leaders in higher education in STEM. Data collection included semi-structured interviews which were theme coded and inductively analysed. RESULTS: The responses and resilience of STEM academics focussed on education appeared to be dependent on interactions between individual disposition in the microsystem and influences of the exosystem and the external macrosystem. Five major themes emerged about the value and quality, scholarship and expertise, progress and mobility, status and identity and community and culture of STEM academics focussed on education. The exosystem was a significant unidirectional influence on STEM academics where judgements were made concerning academic performance, awards, and promotion. Responses of senior leaders in the exosystem were influenced by the macrosystem and culture of science. Academics focussed on research, rather than education were more valued and more likely to be both financially rewarded and promoted. CONCLUSION: During this pressured decade, where COVID-19 has intensified stress, more attention on the direction and reciprocal relationships in the socio-ecological model of higher education is needed in order for educational reform in higher education STEM to be effective. Resilience of STEM academics to educational reform in higher education is a dynamic quality, and the capacity to "bounce back", learn from challenges, and realise expectations of educational reform will depend on an understanding of resilience and support of Bronfenbrenner's spheres of influence.

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.

Adenotonsillar surgery in morbidly obese children: routine elective admission of all patients to the intensive care unit is unnecessary.

Morbidly obese children undergoing adenotonsillectomy, often with co-morbid obstructive sleep apnoea, may be considered at a higher risk of postoperative respiratory compromise. This retrospective study aimed to assess the frequency and severity of postoperative respiratory complications in these patients and to identify preoperative risks factors for such morbidity. Medical and nursing chart review of all consecutive elective post-adenotonsillectomy admissions of morbidly obese children (defined as >95th centile for body mass index adjusted for age and gender) to our intensive care unit over a 30-month period was performed. A total of 26 morbidly obese children were identified. The majority (14/26) had an uncomplicated recovery following surgery. Of those cases that required postoperative intervention, 10 patients required supplemental oxygen with or without suctioning and/or repositioning alone, whilst two required continuous positive airway pressure therapy. No patient required re-intubation. An oxygen saturation nadir of < 70% and the presence of more than one central apnoea, noted on preoperative overnight polysomnography, were associated with postoperative respiratory complications requiring intervention. Although the intervention group were younger, more obese and had a higher respiratory disturbance index, none of these factors were statistically significant. Routine admission to the paediatric intensive care unit of all morbidly obese children undergoing adenotonsillectomy may be unnecessary, once a suitable high level of nursing is available in an alternative setting, to administer simple positional and suctioning intervention and to perform regular patient observation. Special consideration should be given to the postoperative nursing environment for those patients with a SaO2 nadir < 70% noted preoperatively, indicating the presence of a significant central disease component.

Systemic ototoxicity: a review.

BACKGROUND: Systemic ototoxicity is a significant cause of vestibulocochlear morbidity in sub-Saharan Africa. It may result in permanent hearing impairment and/or balance problems. OBJECTIVES: To review the literature pertaining to the ototoxic potential of three frequently prescribed systemic medications in the sub-Saharan setting; quinine, furosemide and aminoglycoside antibiotics. The pathophysiology, clinical manifestations and risk factors and risk minimisation strategies regarding the ototoxicity associated with these drugs are presented in order to highlight this problem and reduce the incidence of adverse outcomes. DATA SOURCES: The biomedical literature was systematically reviewed. This included a search of the National Library of Medicine's PubMed database (http://www.ncbi.nlm.nih.gov/ entrez/query.fcgi?db=PubMed). The search was limited to the English language literature and used the following search terms: ototoxicity; aminoglycosides; quinine; furosemide; gentamicin; vestibular toxicity; auditory toxicity; and Africa. STUDY SELECTION: Studies and reviews directly addressing clinical ototoxicity, experimental studies and studies regarding ototoxicity in sub-Saharan Africa were reviewed. The authors formed a consensus opinion regarding the most relevant articles considering factors including evidence level. DATA EXTRACTION: Systematic data extraction was undertaken from relevant studies. CONCLUSIONS: Quinine, furosemide and aminoglycosides are potentially ototoxic. High doses, prolonged treatment and intravenous administration increase this risk. The clinical condition of the patient may further predispose patients to ototoxic damage. Lack of monitoring facilities and efficacious, cost effective alternatives increase the risks of ototoxicity in the African setting. Clinicians must be aware of these risks and those patients at increased risk, and be vigilant in recognising their clinical manifestations.

Outcomes of myringoplasty in Australian Aboriginal children and factors associated with success: a prospective case series.

The objective of this study was to assess the outcomes of myringoplasties in Aboriginal children and to identify factors associated with a successful outcome with the use of prospective case series from primary health care clinics and hospitals in four rural and remote regions of Western Australia. All 58 Aboriginal children, aged 5-15 years, who underwent 78 myringoplasties between 1 January 2000 and 30 June 2001 were included in the study. Complete postoperative (post-op) follow-up was achieved following 78% of myringoplasties. The main outcome measures were (a) success, i.e. an intact tympanic membrane and normal hearing six or more months post-op in the operated ear, (b) closure of the perforation, (c) Post-op hearing improvement. Forty-nine per cent of myringoplasties were successful, 72% resulted in closure or reduction in the size of the perforation and 51% resulted in hearing improvement. After controlling for age, sex, clustering and number of previous myringoplasties, no association was observed between success or hearing improvement and perforation size, or the presence of serous aural discharge at the time of surgery. Myringoplasty resulted in hearing improvement and/or perforation closure in a significant proportion of children. Thus, primary school-aged Aboriginal children in whom conservative management of chronic suppurative otitis media has been unsuccessful should have access to myringoplasty because of the positive impact on their socialization, language and learning that results from improved hearing.

Management of pseudo-aneurysm of a lateral aberrant internal carotid artery.

A 4-year old boy scheduled for insertion of ventilation tubes suffered significant aural hemorrhage following incision of the tympanic membrane. Examination under anaesthetic resulted in further hemorrhage. Investigation by carotid angiography revealed an anomalous internal carotid artery coursing through the middle ear with a small pseudoaneurysm. Subsequent management of this patient and review of the literature is presented.

Nasal obstruction in the neonate and infant.

The neonate is a preferential nasal breather; therefore, nasal obstruction in the neonatal period may cause significant sequelae. Although the uncommon choanal atresia is the main condition to be excluded, many other possible causes exist. A systematic approach to the workings of nasal obstruction in the neonate and infant is outlined so that appropriate management can be instituted.

Epstein-Barr virus-associated antigens in nasopharyngeal carcinoma.

Thirty-five sera from American patients with nasopharyngeal carcinoma were examined for Epstein-Barr virus (EBV)-associated antigens and compared with 85 sera from patients with other head and neck cancers, 80 sera from patients with lymphoma, and 47 sera from healthy control subjects. There was a definite correlation between the presence of nasopharyngeal carcinoma and the level of antibody titers to EBV. In particular, two tests that detected antibody to early antigen and antibody to viral capsid antigen in the serum IgA fraction were highly specific for the presence of nasopharyngeal carcinoma. There was a significant decrease in these antibody titers with clinical remission of the disease in treated patients with nasopharyngeal carcinoma. Clinically, these tests should have important application in the management and follow-up of patients with nasopharyngeal carcinoma.

Immunovirologic assessment of American patients with nasopharyngeal carcinoma and occult primary tumors.

The Epstein-Barr virus (EBV) is closely associated with nasopharyngeal carcinoma, suggesting an etiologic relationship. We have under-taken studies (1) to quantitate the relationship between antibody titers to EBV-associated antigens and nasopharyngeal carcinoma in American patients since most of the patients in previous studies were of either Asian or African descent and (2) to determine the relationship between antibody titers and the clinical course of the disease. Sera from patients with primary or recurrent nasopharyngeal carcinoma and from patients in remission, from patients with various other head and neck tumors (including occult primary lesions and lymphomas), and from normal controls were titrated for IgG antibodies to viral capsid antigen (VCA) and early antigen and IgA antibodies to VCA, using indirect immunofluorescence procedures previously detailed. High titers of antibodies to EBV-induced early antigens and VCA in the IgG fraction and VCA in the IgA fraction were frequently found in the sera of patients with nasopharyngeal carcinoma. A significant reduction in these titers was observed with clinical remission of the disease in treated patients. Preliminary findings suggest that EBV serology may be useful in the evaluation and treatment of patients with nasopharyngeal carcinoma and also in patients with cervical metastases from clinically occult promary sites in order to identify those with occult nasopharyngeal carcinoma.

An immunologic basis for detection of occult primary malignancies of the head and neck.

After extensive evaluation of patients with metastatic neck disease and clinically undetectable primary cancer of the head and neck, the clinician is often faced with the difficult question of subsequent management. In this study, sera from 11 patients with clinically occult carcinoma and metastatic lymphadenopathy were studied for Epstein-Barr virus-associated antigens. These were compared with 35 sera from patients with known nasopharyngeal carcinoma at all stages of disease and treatment and with 212 sera from control patients with other head and neck tumors, patients with lymphoma, and normal controls. There was a significant correlation between high antibody titers to Epstein-Barr virus, especially in the serum IgA fraction, and the presence of nasopharyngeal carcinoma. Thus, identification of occult nasopharyngeal carcinoma by immunologic means may have important application in the selective management of the patient with an unknown head and neck primary malignancy.

Clinical evaluation of EBV serology in American patients with nasopharyngeal carcinoma.

There is now extensive immunological, biological and biochemical evidence to support a possible etiological relationship between EBV and NPC in patients from different geographical locations. Besides providing information on the question of etiology, the results from immunological investigations suggest that antibodies to some of the EBV-associated antigens might also be of clinical importance in the diagnosis and prognosis of NPC. To determine the possible clinical application of EBV serology to American NPC, sera from patients seen at the Mayo Clinic and the National Institutes of Health were examined for antibodies to EBV-associated antigens in an effort to identify those parameters which most reliably distinguish NPC from other types of cancer. The results show that high antibody titres to EBV-induced EA and the presence of antibody to EBV antigens in the IgA immunoglobulin fraction were the two most specific discriminating parameters, although neither was infallible. These findings are discussed in relation to future studies that are needed in order to determine the potential clinical value of EBV serology to the diagnosis and prognosis of NPC.

Chondrosarcoma of the nasal cavity, paranasal sinuses, and nasopharynx.

Thirteen patients, six men and seven women, were seen at the Mayo Clinic with chondrosarcomas of the nasal cavity, paranasal sinuses, or nasopharynx in a 25-year period. Nasal obstruction, discharge, and bleeding were the major symptoms and a nasal mass was the most common sign. The typical chondrosarcoma is low in grade but malignant and it arises in the nasal cavity as a large, pale, glistening mass. Local excision was employed initially in seven patients and five had local recurrence. Definitive block excision cured four of six patients and the two others had a protracted clinical course and ultimately died of the disease. Long-term follow-up shows that chondrosarcomas are insidious, locally progressive tumors. Radiotherapy, used for palliation after recurrence, failed to produce any cures. Lateral rhinotomy and block excision are advocated as the primary treatment.

Blood pressure in Seventh-day Adventist vegetarians.

The blood pressures (BP) in 418 vegetarian Seventh-day Adventist (SDA) volunteers in Western Australia were compared with those in 290 non-vegetarian volunteers in Narrogin, a Western Australian country town. The mean systolic and diastolic BPs in the SDAs, adjusted for age, sex, height and weight (128.7/76.2 mm of mercury) were significantly less than those in the Narrogin residents (139.3/84.5). It appeared unlikely that these differences could be explained by differences in alcohol, tobacco, tea, coffee or egg consumption, socioeconomic status or physical activity. There was, however, a gradient toward increasing BP with increasing egg intake in SDAs, and SDAs who drank tea or coffee had a higher mean diastolic BP than those who did not (mean difference of 4.2 mm of mercury). The possibility that selective bias or unmeasured environmental differences might explain the difference in BP between the two groups is discussed.

Carcinoma of the supraglottic larynx. A review of 221 cases.

Between 1962 and 1971, 221 patients (197 men and 24 women) with carcinoma of the supraglottic larynx were treated at our institution. Most of the patients were in the sixth and seventh decades of life. In 89% of the patients, the epiglottis was involved. One hundred ninety patients underwent surgery, 161 for cure initially and 29 for salvage after radiation failure. Definitive surgery included laryngectomy in 117 patients and conservation procedures in 40. Fifty-five patients were treated by radiation for cure. Survival rates after laryngectomy or supraglottic laryngectomy were similar, but radiation therapy carried a poorer prognosis than did definitive surgery. Routine neck dissection was not necessary in all patients with supraglottic carcinoma.

Granular cell tumors of the larynx.

Granular cell tumors of the larynx are relatively uncommon, always benign, and most commonly located in the posterior portion of the larynx. They are easily identified and should be differentiated from other lesions. A possible problem in the differential diagnosis is the presence of pseudoepitheliomatous hyperplasia, which overlies the granular cell tumor and which may mimic squamous cell carcinoma. Careful histopathologic differentiation is important because the laryngeal granular cell lesion should be managed conservatively, with transoral local excision usually being adequate. The histogenesis of these lesions remains in doubt, with a neural or epithelial derivation being the most likely possibility.