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.

Diversity of nontypeable Haemophilus influenzae strains colonizing Australian Aboriginal and non-Aboriginal children.

Nontypeable Haemophilus influenzae (NTHI) strains are responsible for respiratory-related infections which cause a significant burden of disease in Australian children. We previously identified a disparity in NTHI culture-defined carriage rates between Aboriginal and non-Aboriginal children (42% versus 11%). The aim of this study was to use molecular techniques to accurately determine the true NTHI carriage rates (excluding other culture-identical Haemophilus spp.) and assess whether the NTHI strain diversity correlates with the disparity in NTHI carriage rates. NTHI isolates were cultured from 595 nasopharyngeal aspirates collected longitudinally from asymptomatic Aboriginal (n=81) and non-Aboriginal (n=76) children aged 0 to 2 years living in the Kalgoorlie-Boulder region, Western Australia. NTHI-specific 16S rRNA gene PCR and PCR ribotyping were conducted on these isolates. Confirmation of NTHI by 16S rRNA gene PCR corrected the NTHI carriage rates from 42% to 36% in Aboriginal children and from 11% to 9% in non-Aboriginal children. A total of 75 different NTHI ribotypes were identified, with 51% unique to Aboriginal children and 13% unique to non-Aboriginal children (P<0.0001). The strain richness (proportion of different NTHI ribotypes) was similar for Aboriginal (19%, 65/346) and non-Aboriginal children (19%, 37/192) (P=0.909). Persistent carriage of the same ribotype was rare in the two groups, but colonization with multiple NTHI strains was more common in Aboriginal children than in non-Aboriginal children. True NTHI carriage was less than that estimated by culture. The Aboriginal children were more likely to carry unique and multiple NTHI strains, which may contribute to the chronicity of NTHI colonization and subsequent disease.

A clinical evaluation of four non-Luer spinal needle and syringe systems.

We performed an evaluation of non-Luer spinal devices supplied by four manufacturers or suppliers: Polymedic; Pajunk; Sarstedt; and Smiths. For each supplier, 100 evaluations were performed using a 25-G 90-mm spinal needle, 3-ml syringe, 5-ml syringe and filter needle; for comparison, 100 evaluations were performed with our standard Luer equipment. The non-Luer devices were associated with more qualitative problems compared with the Luer devices, for example, poor feel of dural puncture (9-32% vs 10%, respectively), poor observation of cerebrospinal fluid in the hub (3-27% vs 0%), and connection problem of the syringe to the spinal needle (7-33% vs 0%). There was also more frequent failure to achieve the spinal injection due to equipment-related causes (4-7% vs 0%, respectively). Median (IQR [range]) numeric satisfaction scores for the spinal needles were: Luer 10 (9-10 [7-10]); Polymedic 7 (4-8 [0-10]; Pajunk 7 (5-8 [0-10]); Sarstedt 7 (6-8 [0-10]); and Smiths 9 (7-10 [0-10]) (p<0.0001). Satisfaction scores for all spinal equipment were: Luer 10 (9-10 [5-10]); Polymedic 8 (6-8 [0-10]); Pajunk 7 (5-7 [1-9]); Sarstedt 8 (6-8 [0-10]); and Smiths 8 (8-9 [2-10]) (p<0.0001). Between 21% and 75% of non-Luer evaluations were rated with satisfaction worse than the usual Luer needle compared with 0-10% rated better, depending on the needle type. Between 22% and 76% of non-Luer evaluations were rated with satisfaction worse than the usual Luer equipment compared with 0-14% rated better. Specific concerns included poor feel of tissue planes and observation of cerebrospinal fluid (Polymedic), difficulty with connection of the syringe to the spinal needle and trocar removal (Pajunk), poor feel of tissue planes and needle flexibility (Sarstedt) and difficulty with connection of the syringe to the spinal needle (Smiths). We could not demonstrate a short-term learning curve for the new devices. Decisions on purchasing and implementation of the new non-Luer equipment will have to acknowledge that clinicians may have greater technical problems and reduced satisfaction compared with the current equipment.

Trivalent influenza vaccine and febrile adverse events in Australia, 2010: clinical features and potential mechanisms.

INTRODUCTION: Increased numbers of children presenting with febrile adverse events following trivalent influenza vaccine (TIV) were noted in Australia in 2010. We describe the epidemiology and clinical features of the adverse events and explore the biological basis for the adverse events using an in vitro model. MATERIALS AND METHODS: Children presenting to a tertiary paediatric hospital in 2010 with adverse events within 72 h of TIV were retrospectively reviewed. Demographics, clinical features, physiological variables and outcomes were examined. Plasma cytokine and chemokine levels were examined in a subgroup of children with vaccine-related febrile convulsions. Peripheral blood mononuclear cells of age-matched children were stimulated with different TIV preparations. Inflammatory cytokine and chemokine analysis was performed on cultured supernatants. RESULTS: Vaccine-related febrile adverse events were identified in 190 children. Most occurred in healthy children (median age: 1.5 years) within 12 h of vaccination. Twenty-eight (14.7%) required hospital admission. High temperature ≥39.0 °C (101/190; 53%), vomiting (120/190; 63%) and convulsions (38/190; 20%) were common. All children presenting had received Fluvax(®) or Fluvax Junior(®). In the in vitro model, IFN-α, IL-1ß, IL-6, IL-10, IP-10 and MIP-1α levels were significantly higher when measured at 6 and 24 h in cultures stimulated with Fluvax(®) compared with alternative 2010 TIV preparations. CONCLUSIONS: Numerous febrile adverse events (including febrile seizures) were observed following Fluvax(®) or Fluvax Junior(®) in 2010. Clear differences in cytokine production were observed when peripheral blood mononuclear cells were stimulated with Fluvax(®) compared with alternate TIV preparations. Increased awareness of these potential adverse events is required to ensure earlier detection and prevention in the future.

Case of the month: A case of airway obstruction following tenecteplase administration.

The value of thrombolysis in the treatment of acute myocardial infarction is well established. Haemorrhage into subcutaneous tissues is fortunately a rare complication of fibrinolytic administration. However, if as a result of trauma a haematoma develops within the neck following thrombolysis, it can lead to rapid airway compromise. This is the first reported case of tenecteplase administration leading to subcutaneous haemorrhage and consequent airway compromise. It is also the first reported case where the antecedent trauma was a jaw thrust.

Functional expression cloning reveals proapoptotic role for protein phosphatase 4.

Functional expression cloning strategies are highly suitable for the analysis of the molecular control of apoptosis. This approach has two critical advantages. Firstly, it eliminates prior assumptions about the properties of the proteins involved, and, secondly, it selectively targets proteins that are causally involved in apoptosis control and which affect the crucial cellular decision between survival and death. The application of this strategy to the isolation of cDNAs conferring resistance to dexamethasone and gamma-irradiation resulted in the isolation of a partial cDNA for the catalytic subunit of protein phosphatase 4 (PP4). Cells transfected with this partial cDNA in an expression vector downregulated PP4 and were resistant to both dexamethasone and UV radiation, as demonstrated by both membrane integrity and colony-forming assays. These observations suggest that PP4 plays an important proapoptotic role in T lymphocytes.

Surgical cleft soft palate repair in a foal.

An Anglo-Arab foal with bilateral postprandial nasal discharge was diagnosed as having a full-length defect of the soft palate. Surgical repair was attempted using a combination of two surgical approaches. Initially a mandibular symphysiotomy approach was used. The posterior portion of the defect did not heal adequately, so a ventral laryngotomy, bisecting the body of the thyroid cartilage and extending to a pharyngotomy approach, was performed 5 months later. The foal has since matured fully despite a slight unilateral nasal discharge. This case report demonstrates that these two surgical approaches used simultaneously provide surgical access that is superior to either approach used individually.

The SbcCD nuclease of Escherichia coli is a structural maintenance of chromosomes (SMC) family protein that cleaves hairpin DNA.

Hairpin structures can inhibit DNA replication and are intermediates in certain recombination reactions. We have shown that the purified SbcCD protein of Escherichia coli cleaves a DNA hairpin. This cleavage does not require the presence of a free (3' or 5') DNA end and generates products with 3'-hydroxyl and 5'-phosphate termini. Electron microscopy of SbcCD has revealed the "head-rod-tail" structure predicted for the SMC (structural maintenance of chromosomes) family of proteins, of which SbcC is a member. This work provides evidence consistent with the proposal that SbcCD cleaves hairpin structures that halt the progress of the replication fork, allowing homologous recombination to restore DNA replication.