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Rationale: In adults, obstructive sleep apnea (OSA) is associated with metabolic dysfunction that improves with treatment of OSA. No equivalent studies exist in children.Objective: To examine the relationship between metabolic markers and OSA with time and treatment in children.Methods: Metabolic markers measured on a fasting morning blood sample at diagnostic polysomnography and follow-up 1.3 +/- 0.6 yr later.Measurements and Main Results: Forty-five children (34 males), aged 6.9 +/- 3.5 yr, and including 12 obese subjects, were in the final analysis. There were no differences in metabolic markers between children with and without OSA at initial study; however, obese children had significantly higher insulin (106.1 +/- 72.1 vs. 66.7 +/- 37.6 pmol/L; p = 0.028), insulin/glucose ratio (23.7 +/- 14.3 vs. 14.7 +/- 8.0; p = 0.02), and significantly lower high-density lipoprotein cholesterol (1.3 +/- 0.2 vs. 1.6 +/- 0.4 nmol/L; p = 0.005) than nonobese children. Twenty children underwent surgical removal of adenotonsillar tissue, whereas 12 children with OSA elected not to have treatment. OSA persisted after treatment in five children, and resolved in 27. Thirteen children did not have OSA on initial or follow-up studies. At follow-up, there was a small but significant improvement in total cholesterol in those children whose OSA was resolved (4.8 +/- 0.8 to 4.7 +/- 0.6 nmol/L; p = 0.005) and a trend for obese children with persisting OSA to have elevated insulin levels compared with obese children without OSA (p = 0.07).Conclusion: Obesity appears to be the major influence on metabolic dysfunction in children with OSA, but these preliminary data also suggest that resolution or persistence of OSA may affect changes in metabolic function over time. [ABSTRACT FROM AUTHOR]

Trans-sulcal minimally invasive parafascicular surgery is an emerging technique to approach deep lesions with minimal brain retraction. Localization of the tubular retractor during surgery is critical, and intraoperative magnetic resonance imaging and neuronavigation present limitations. We describe the intraoperative use of O-Arm® coupled with pre-operative tractography to precisely localize the tubular retractor. With air acting as contrast, the tubular retractor was localized in three dimensions, without any additional disruption to white matter tracts or nearby vascular structures. We conclude that visualization of tubular retractor using an intraoperative computerized tomography scan is a safe and feasible adjunct in resection of deep lesions via a minimally invasive approach., Competing Interests: The authors do not have any conflict of interest to declare., (Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2024.)

Background: Bladder and urinary tract cancers account for approximately 21,000 new diagnoses and 5,000 deaths annually in the UK. Approximately 90% are transitional cell carcinomas where advanced disease is treated with platinum based chemotherapy and PD-1/PD-L1 directed immunotherapy. Urinary tract squamous cell carcinoma (UTSCC) accounts for about 5% of urinary tract cancers overall making this a rare disease. We have yet to establish definitive systemic treatment options for advanced UTSCC. Preliminary translational data, from UTSCC patient tumour samples, indicate high PD-L1 expression and tumour infiltrating lymphocytes in a proportion of cases. Both of these features are associated with differential gene expression consistent with a tumour/immune microenvironment predicted to be susceptible to immune checkpoint directed immunotherapy which we will evaluate in the AURORA trial., Methods: AURORA is a single arm, open-label, multicentre,UK phase II clinical trial. 33 patients will be recruited from UK secondary care sites. Patients with UTSCC, suitable for treatment with palliative intent, will receive atezolizumab PD-L1 directed immunotherapy (IV infusion, 1680 mg, every 28 days) for one year if tolerated. Response assessment, by cross sectional imaging will occur every 12 weeks. AURORA uses a Simon's 2-stage optimal design with best overall objective response rate (ORR, by RECIST v1.1) at a minimum of 12 weeks from commencing treatment as the primary endpoint. Secondary endpoints will include overall survival, progression-free survival, duration of response, magnitude of response using waterfall plots of target lesion measurements, quality of life using the EORTC QLQ-C30 tool, safety and tolerability (CTCAE v5) and evaluation of potential biomarkers of treatment response including PD-L1 expression. Archival tumour samples and blood samples will be collected for translational analyses., Discussion: If this trial shows atezolizumab to be safe and effective it may lead to a future late phase randomised controlled trial in UTSCC. Ultimately, we hope to provide a new option for treatment for such patients., Trial Registrations: EudraCT Number: 2021-001995-32 (issued 8 th September 2021); ISRCTN83474167 (registered 11 May 2022); NCT05038657 (issued 9th September 2021)., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Purpose: We report what we believe is the first application of robotically constrained image-guided surgery to approach a fistulous micro-arteriovenous malformation in a highly eloquent location. Drawing on institutional experience with a supervisory-control robotic system, a series of steps were devised to deliver a tubular retractor system to a deeply situated micro-arteriovenous malformation. The surgical footprint of this procedure was minimised along with the neurological morbidity. We hope that our contribution will be of assistance to others in integrating such systems given a similar clinical problem., Clinical Presentation: A right-handed 9-year old girl presented to her local emergency department after a sudden onset of severe headache accompanied by vomiting. An intracranial haemorrhage centred in the right centrum semiovale with intraventricular extension was evident and she was transferred urgently to the regional paediatric neurosurgical centre, where an external ventricular drain (EVD) was sited. A digital subtraction angiogram demonstrated a small right hemispheric arteriovenous shunt irrigated by peripheral branches of the middle cerebral artery & a robotically facilitated parafasicular microsurgical approach was performed to disconnect the arteriovenous malformation., Conclusion: We describe the successful microsurgical in-situ disconnection of a deeply-situated, fistulous micro-AVM via a port system itself delivered directly to the target with a supervisory-control robotic system. This minimised the surgical disturbance along a relatively long white matter trajectory and demonstrates the feasibility of this approach for deeply located arteriovenous fistulae or fistulous AVMs.

The use of dengue virus (DENV) vaccines has been hindered by the complexities of antibody dependent enhancement (ADE). Current late-stage vaccine candidates utilize attenuated and chimeric DENVs that produce particles of varying maturities. Antibodies that are elicited by preferentially exposed epitopes on immature virions have been linked to increased ADE. We aimed to further understand the humoral immunity promoted by DENV particles of varying maturities in an AG129 mouse model using a chimeric insect specific vaccine candidate, bDENV-2. We immunized mice with mature, partially mature, and immature bDENV-2 and found that immunization with partially mature bDENV-2 produced more robust and cross-neutralizing immune responses than immunization with immature or mature bDENV-2. Upon challenge with mouse adapted DENV-2 (D220), we observed 80% protection for mature bDENV-2 vaccinated mice and 100% for immature and partially mature vaccinated mice, suggesting that protection to homotypic challenge is not dependent on maturation. Finally, we found reduced in vitro ADE at subneutralising serum concentrations for mice immunized with mature bDENV-2. These results suggest that both immature and mature DENV particles play a role in homotypic protection; however, the increased risk of in vitro ADE from immature particles indicates potential safety benefits from mature DENV-based vaccines.

Flaviviruses are the cause of severe human diseases transmitted by mosquitoes and ticks. These viruses use a potent fusion machinery to enter target cells that needs to be restrained during viral assembly and egress. A molecular chaperone, premembrane (prM) maintains the virus particles in an immature, fusion-incompetent state until they exit the cell. Taking advantage of an insect virus that produces particles that are both immature and infectious, we determined the structure of the first immature flavivirus with a complete spike by cryo-electron microscopy. Unexpectedly, the prM chaperone forms a supporting pillar that maintains the immature spike in an asymmetric and upright state, primed for large rearrangements upon acidification. The collapse of the spike along a path defined by the prM chaperone is required, and its inhibition by a multivalent immunoglobulin M blocks infection. The revised architecture and collapse model are likely to be conserved across flaviviruses., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Objectives: Efforts to develop and deploy effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue at pace. Here, we describe rational antigen design through to manufacturability and vaccine efficacy of a prefusion-stabilised spike (S) protein, Sclamp, in combination with the licensed adjuvant MF59 'MF59C.1' (Seqirus, Parkville, Australia)., Methods: A panel recombinant Sclamp proteins were produced in Chinese hamster ovary and screened in vitro to select a lead vaccine candidate. The structure of this antigen was determined by cryo-electron microscopy and assessed in mouse immunogenicity studies, hamster challenge studies and safety and toxicology studies in rat., Results: In mice, the Sclamp vaccine elicits high levels of neutralising antibodies, as well as broadly reactive and polyfunctional S-specific CD4 + and cytotoxic CD8 + T cells in vivo . In the Syrian hamster challenge model ( n  = 70), vaccination results in reduced viral load within the lung, protection from pulmonary disease and decreased viral shedding in daily throat swabs which correlated strongly with the neutralising antibody level., Conclusion: The SARS-CoV-2 Sclamp vaccine candidate is compatible with large-scale commercial manufacture, stable at 2-8°C. When formulated with MF59 adjuvant, it elicits neutralising antibodies and T-cell responses and provides protection in animal challenge models., Competing Interests: KJC, DW and PRY are inventors of the ‘Molecular Clamp’ patent, US 2020/0040042., (© 2021 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

There are no approved flaviviral therapies and the development of vaccines against flaviruses has the potential of being undermined by antibody-dependent enhancement (ADE). The flavivirus nonstructural protein 1 (NS1) is a promising vaccine antigen with low ADE risk but has yet to be explored as a broad-spectrum therapeutic antibody target. Here, we provide the structural basis of NS1 antibody cross-reactivity through cocrystallization of the antibody 1G5.3 with NS1 proteins from dengue and Zika viruses. The 1G5.3 antibody blocks multi-flavivirus NS1-mediated cell permeability in disease-relevant cell lines, and therapeutic application of 1G5.3 reduces viremia and improves survival in dengue, Zika, and West Nile virus murine models. Finally, we demonstrate that 1G5.3 protection is independent of effector function, identifying the 1G5.3 epitope as a key site for broad-spectrum antiviral development., (Copyright © 2021, American Association for the Advancement of Science.)

Background: High-concentration oxygen therapy causes increased arterial partial pressure of carbon dioxide (PaCO 2 ) in patients with COPD, asthma, pneumonia, obesity and acute lung injury. The objective of these studies was to investigate whether this physiological response to oxygen therapy occurs in stable patients with neuromuscular disease or kyphoscoliosis, and bronchiectasis., Methods: Three randomised cross-over trials recruited stable patients with neuromuscular disease or kyphoscoliosis (n = 20), bronchiectasis (n = 24), and COPD (n = 24). Participants were randomised to receive 50% oxygen and 21% oxygen (air), each for 30 min, in randomly assigned order. The primary outcome was transcutaneous partial pressure of carbon dioxide (PtCO 2 ) at 30 min. The primary analysis was a mixed linear model., Results: Sixty six of the 68 participants had baseline PtCO 2 values < 45 mmHg. The intervention baseline adjusted PtCO 2 difference (95% CI) between oxygen and room air after 30 min was 0.2 mmHg (- 0.4 to 0.9), P = 0.40; 0.5 mmHg (- 0.2 to 1.2), P = 0.18; and 1.3 mmHg (0.7 to 1.8), P < 0.001, in the neuromuscular/kyphoscoliosis, bronchiectasis and COPD participants respectively., Conclusions: The small increase in PtCO 2 in the stable COPD patients with high-concentration oxygen therapy contrasts with the marked increases in PaCO 2 seen in the setting of acute exacerbations of COPD. This suggests that the model of studying the effects of high-concentration oxygen therapy in patients with stable respiratory disease is not generalisable to the use of oxygen therapy in the acute clinical setting. Appropriate studies of high-concentration compared to titrated oxygen in acute clinical settings are needed to determine if there is a risk of oxygen-induced hypercapnia in patients with neuromuscular disease, kyphoscoliosis or bronchiectasis., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12615000970549 Registered 16/9/15, ACTRN12615000971538 Registered 16/9/15 and ACTRN12615001056583 Registered 7/10/15.

Birds have a ZZ male and ZW female sex chromosome system. The relative roles of genetics and hormones in regulating avian sexual development have been revealed by studies on gynandromorphs. Gynandromorphs are rare bilateral sex chimeras, male on one side of the body and female on the other. We examined a naturally occurring gynandromorphic chicken that was externally male on the right side of the body and female on the left. The bird was diploid but with a mix of ZZ and ZW cells that correlated with the asymmetric sexual phenotype. The male side was 96% ZZ, and the female side was 77% ZZ and 23% ZW. The gonads of this bird at sexual maturity were largely testicular. The right gonad was a testis, with SOX9+ Sertoli cells, DMRT1+ germ cells, and active spermatogenesis. The left gonad was primarily testicular, but with some peripheral aromatase-expressing follicles. The bird had low levels of serum estradiol and high levels of testosterone, as expected for a male. Despite the low percentage of ZW cells on that side, the left side had female sex-linked feathering, smaller muscle mass, smaller leg and spur, and smaller wattle than the male side. This indicates that these sexually dimorphic structures must be at least partly independent of sex steroid effects. Even a small percentage of ZW cells appears sufficient to support female sexual differentiation. Given the lack of chromosome-wide dosage compensation in birds, various sexually dimorphic features may arise due to Z-gene dosage differences between the sexes.

Background and Objective: Increased arterial carbon dioxide tension (PaCO 2 ) is an important complication of acute exacerbations of COPD. The effects of nasal high-flow cannulae (NHF) on PaCO 2 in patients with COPD exacerbations, and whether this therapy should be used in this clinical situation, are less certain. We aimed to investigate the effect of NHF on PaCO 2 in patients admitted to hospital with a COPD exacerbation., Methods: We performed a single-centre randomized controlled cross-over trial in 24 hospital inpatients with acute exacerbations of COPD receiving oxygen via standard nasal prongs (SNPs). Patients received both supplemental oxygen via NHF (35 L/min) and SNP for 30 min each, with oxygen titrated to maintain the patient's baseline oxygen saturation, measured by pulse oximetry (SpO 2 ). Interventions were administered in random order with a minimum 15-min washout between interventions. The primary outcome was difference in transcutaneous carbon dioxide tension (PtCO 2 ) at 30 min adjusted for time zero., Results: The difference in PtCO 2 adjusted for time zero was lower after 30 min for NHF compared with SNP (-1.4 mm Hg (95% CI: -2.2 to -0.6), P = 0.001). There was no difference in SpO 2 at 30 min (-0.02% (95% CI: -0.8 to 0.7), P = 0.96). The reduction in respiratory rate for NHF at 30 min was not statistically significant (-2.0 breaths/min (95% CI: -4.5 to 0.4), P = 0.099)., Conclusion: Short-term use of NHF results in a small reduction in PtCO 2 compared with SNP in patients with acute exacerbations of COPD, but whether this is clinically significant is uncertain., (© 2017 Asian Pacific Society of Respirology.)

Objectives: Delivery of warmed, humidified air via nasal high flow therapy could potentially reduce replication of temperature-sensitive viruses in the upper respiratory tract. This study investigates whether nasal high flow therapy is well tolerated by healthy adults at 37°C and 41°C., Methods: In this randomised, double-blind, controlled crossover pilot trial, nasal high flow therapy was used to deliver humidified air at 35 L/min, at either 37°C or 41°C, for three one-hour sessions of use over one day. The alternative was delivered at least 14 days later. Ten healthy, nonsmoking adults were asked, via questionnaire after each day's use, whether they would use nasal high flow therapy while being unwell with a cold or flu if it was demonstrated to improve symptoms., Results: All participants completed both interventions. Eighty percent responded "yes" to future use of nasal high flow therapy, for both 37°C and 41°C. There was no significant change from baseline in saccharin times following either intervention or in the following morning., Conclusions: Delivering humidified air via nasal high flow therapy at both 37°C and 41°C is well tolerated by healthy adults. This supports investigation into the potential use of nasal high flow therapy as treatment in viral upper respiratory tract infections. Trial Registration. This trial is registered with ACTRN12614000183684 (tolerability study of nasal delivery of humidified & warmed air).

Aim: To investigate hospital admissions for non-cystic fibrosis bronchiectasis during July 1, 2008 to June 30, 2013; and to describe their distribution and annual cost in New Zealand., Methods: Admissions with a principal diagnosis of bronchiectasis (ICD10 J47), excluding cystic fibrosis, and length of stay <90 days were analysed by age, sex, ethnicity, socioeconomic deprivation, DHB, re-admissions and seasonality., Results: There were 5,494 admissions with a mean annual rate of 25.7 (age adjusted rate 20.4) per 100,000. Admission rates peaked in childhood and in the elderly, and increased steeply with socioeconomic deprivation. Age-adjusted rates were 38% higher for women, 4.9-fold higher for Māori and 9.1-fold higher for Pacific peoples. Counties Manukau had the highest unadjusted rate for any DHB (49.4 per 100,000). The overall 30 day readmission rate was 12.4%. Admissions peaked in winter and spring. The estimated cost in financial year 2012/13 was NZD 5.34M., Conclusion: Hospital admissions for bronchiectasis are concentrated in socioeconomically disadvantaged young and elderly Māori and Pacific peoples; are more common in winter and spring, and incur a high annual cost. Evidence-based interventions to reduce the disproportionate burden of bronchiectasis in Māori and Pacific children and the elderly is a public health priority.

Investigation of ocular disease in a flock of layer pullets identified corneal infection with Scedosporium apiospermum, a fungus of emerging significance in medicine and veterinary medicine., (© 2013 American College of Veterinary Ophthalmologists.)

Background: The clinical significance of antineutrophil cytoplasmic antibodies (ANCAs) in the phenotypic expression of Churg-Strauss syndrome (CSS) is uncertain., Objective: We sought to investigate the relationship between ANCA status and the clinical expression of CSS in a case series derived from the US Food and Drug Administration's adverse events database., Methods: All cases of CSS reported to the US Food and Drug Administration from 1997 to April 2003 were reviewed. Information about basic demographics, suspect medication use, clinical manifestations, histologic findings, ANCA staining patterns, and the presence of antibodies to myeloperoxidase (anti-MPO) or proteinase 3 (anti-PR3) was recorded when available., Results: There were 93 case reports of CSS with sufficient documentation, including ANCA status. There were 38 (40.9%) of 93 cases with positive ANCA results, of which 15 cases reported a positive ELISA, all of which were positive for anti-MPO. ANCA negativity was associated with an increased proportion of cardiac involvement (risk difference [RD], 38.2%; 95% CI, 25.3% to 51.0%), gastrointestinal involvement (RD, 25.5%; 95% CI, 13.9% to 37.0%), pulmonary infiltrates (odds ratio, 4.9; 95% CI, 1.5-16.2), and the outcome of a life-threatening event or death (RD, 30.9%; 95% CI, 18.7% to 43.1%) when compared with anti-MPO-positive cases. ANCA negativity was associated with a decreased proportion of peripheral neuropathy (odds ratio, 0.3; 95% CI, 0.07-0.9)., Conclusion: These findings support the hypothesis that the presence or absence of autoantibodies influences the clinical expression and severity of CSS., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Objective: To report clinical and clinicopathological findings in horses naturally infected with Ross River virus (RRV) and identify likely mosquito arbovirus vector species., Procedures: Veterinarians submitted serum samples from 750 horses because they suspected Ross River virus (RRV) infection. The samples were tested for the presence of IgM and IgG antibody to RRV and for the presence of virus. Mosquitoes were trapped, differentiated to species level and tested for the presence of RRV by virus isolation., Results: RRV was isolated from six species of mosquitoes (Ochlerotatus camptorhyncus, Culex globocoxitus, Cx. australicus, Cx. annulirostris, Cx. quinquefasciatus, Anopheles annulipes) and from 13 horses with clinical signs of musculo-skeletal disease. Antibody to RRV was detected in 420 of the 750 serum samples; 307 contained IgG only; 76 contained both IgM and IgG and 37 contained only IgM antibody to RRV. Virus was isolated from horses with IgM antibody only., Conclusions: RRV can be isolated from infected horses during the short time period when there is an overlap of clinical signs, positive IgM serology and viraemia. Early spring infections of horses may occur if RRV infected mosquito vectors are present. RRV has not been shown to cause clinical disease in horses. This is the first report of isolation of RRV from Oc. camptorhyncus in the Murray region and indicates a potential for infection of humans and animals in autumn as well as in spring.

After a review of disk structure, the pivotal role of disk cells in producing and renewing the extracellular disk matrix is emphasized. Disk cells rely on nutrients that diffuse through the vertebral endplates. Microelectrode methods have been developed to study nutrient diffusion and endplate permeability. Mechanical stimuli modify disk cell activity. Scoliosis is associated with decreased endplate permeability, a factor that may play a role in disk degeneration and scoliosis progression.

Teicoplanin is a new antibiotic currently undergoing extensive investigation to evaluate its potential use in the prophylaxis and treatment of appropriate infection. To ascertain its penetration into the biliary system, 24 patients undergoing elective cholecystectomy were randomised to receive an intravenous bolus of 400 mg teicoplanin 1, 3, 6 or 12 h prior to surgery. During the operation, blood, gall bladder bile and tissue and common bile duct bile were removed for teicoplanin estimation. The results show that teicoplanin penetrates well into the gall bladder wall and bile, though less well into common bile duct bile. These results show that teicoplanin would seem to be a suitable antibiotic for the treatment of biliary infections that are known to be sensitive to the antibiotic.

Teicoplanin is a new antibiotic currently undergoing clinical evaluation. Consecutive patients undergoing elective vascular surgery (n = 28) were randomised to receive a single intravenous bolus of 400 mg teicoplanin 1, 3, 6 or 12 h prior to surgery as prophylaxis against Gram-positive infection. Serum and fat antibiotic levels were measured and found to exceed the established MICs for common staphylococcal and streptococcal infections for at least 12 h following administration. This suggests that teicoplanin would be a useful choice of antibiotic in the prophylaxis and treatment of appropriate infections in elective surgery. By extrapolation, teicoplanin would also be of use in the prophylaxis and treatment of suitable infections seen in traumatised patients.