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• There are multiple areas where error can be introduced into surgical navigation systems for endoscopic skull base surgery. • Geometric distortion has been described as a potential source of error for MRI sequences, but this has not been examined in vivo. • Research should focus on reducing registration error as the error of geometric distortion is not clinically significant. Neuronavigation is common technology used by skull base teams when performing endoscopic endonasal surgery. A common practice of MRI imagining is to obtain 3D isotopic gadolinium enhanced T1W magnetisation prepared rapid gradient echo (MPRAGE) sequences. These are prone to distortion when undertaken on 3 T magnets. The aim of this project is to compare the in vivo accuracy of MRI sequences between current and new high resolution 3D sequences. The goal is to determine if geometric distortion significantly affects neuronavigation accuracy. Patients were scanned with a 3D T1 MPRAGE sequence, 3D T1 SPACE sequence and a CT stereotactic localisation. Following general anaesthesia, patients were registered on the Stealth Station (Medtronic, USA) using a side mount emitter for Electromagnetic navigation. A variety of surgically relevant anatomical landmarks in the sagittal and coronal plane were selected with real and virtual data points measured. A total of 10 patients agreed be enrolled in the study with datapoints collected during surgery. The distance between real and virtual datapoints trended to be lower in SPACE sequences compared to MPRAGE. Paired t test did not demonstrate a significant difference. We have demonstrated that navigational accuracy is not significantly affected by the type of MRI sequence selected and that current corrective algorithms are sufficient. Navigational accuracy is affected by many factors, with registration error likely playing the most significant role. Further research involving real time imaging such as endoscopic ultrasound may hopefully address this potential error. [ABSTRACT FROM AUTHOR]

• Achieving a positive endocrine outcome for patients with non-functional adenomas continues to make small incremental improvements even during the 'plateau' phase of the learning curve. • Some metrics such as degree of resection can significantly improve as surgical experience increases. • More research should focus on ways of shortening the learning curve to allow junior neurosurgeons the ability to deliver high quality endocrine outcomes more efficiently. In South Australia endoscopic endonasal approach (EEA) pituitary surgery has been practiced since 2006, largely by two neurosurgeons with a small fellowship-trained otolaryngology team. The aim of this cohort study was to determine if a "learning curve" can be established over this time period, as represented by structural and endocrine patient outcomes. Retrospective cohort study of patients undergoing EEA surgery between 2006 and 2021 in Adelaide, South Australia at three tertiary teaching hospitals.. Cases were divided by each surgeon and split into groups of sequential 40 cases. Endocrine assessment pre- and post-operatively involved static pituitary and end-organ hormones, with dynamic tests as required, assessed by an pituitary endocrinologist. Each hormonal axis (gonadal, cortisol, thyroid, prolactin and growth hormone) was documented preoperatively and at an early and long term follow up at 1–2 and 12 months, respectively. The study included a cohort of 443 pituitary adenomas managed with endoscopic endonasal transsphenoidal surgery in a consecutive fashion between two neurosurgeons over 16-years. Gross tumour resection but not visual visual outcomes improved with surgical experience but this outcome may be neurosurgeon dependent. Endocrine outcomes were not consistently improved with experience, but lower rates of hypopituitarism were seen with experience with one neurosurgeon. Average follow up was approximately 5 years, and a minimum follow up of 12 months for all patients. We present long term endocrine follow up for patients with functional and non-functional adenomas. Improved rates of gross tumour resection were evident with with surgical experience. However, there was no apparent change in post-operative endocrine outcomes. [ABSTRACT FROM AUTHOR]

• Small vessel injury management in the endoscopic surgical setting has under recognised clinical significance. • Small vessel injury management agents include bipolar cautery, flowable haemostatic agents, and patches. • A novel beta-chitin patch has shown significant benefits in other clinical settings – however within the CNS, it shows deleterious effects such as neuronal degeneration, fibrosis. • Widely used agents of Floseal and Bipolar cautery also cause similar reactions against cerebral tissue however to a lesser degree. Rapid and efficacious haemostasis is paramount in neurosurgery. Assessing the efficacy and short- and long-term safety of haemostatic agents utilised within cerebral tissue is essential. This pilot study investigates the haemostatic efficacy and long-term safety of a novel beta-chitin patch against traditionally used agents, bipolar and Floseal, within cerebral tissue. Eighteen Merino sheep underwent standardised distal cortical vessel injury via temporal craniotomy. Sheep were randomised to receive 2 mls Floseal, 2 cm novel beta-chitin patch, or bipolar cautery to manage bleeding. All sheep underwent cerebral magnetic resonance imaging (MRI) at three months, before euthanasia and brain harvesting for histological assessment. Beta-chitin demonstrated a trend towards a faster mean time to haemostasis (TTH) compared to Floseal (223.3 ± 199 s v. 259.8 ± 186.4 s), albeit non-significant (p = 0.234). Radiologically, cerebrocortical necrosis (p = 0.842) and oedema (p = 0.368) were noted slightly more frequently in the beta-chitin group. Histologically, severe fibrotic (p = 0.017) and granulomatous changes at the craniotomy sites were only present in the beta-chitin group (p = 0.002). Neuronal degeneration was seen in all with Floseal, but beta-chitin showed a trend towards more severe reaction when present. Bipolar use predominantly showed an inflammatory cortical reaction with substantial microvascular proliferation, and Floseal showed worse severity and depth of subpial oedema, however no statistical significance was reached. All haemostats controlled bleeding, with beta-chitin demonstrating a non-inferior TTH compared to Floseal. However, it resulted in intense granulomatous and fibrotic changes, including degenerative neuronal reactions. More extensive studies are needed to assess these trends, to make further clinical inferences. [ABSTRACT FROM AUTHOR]

• Chitosan utilizes multiple mechanisms in order to induce hemostasis. • Clinical research on the use of chitosan in neurosurgical use is lacking. • In vivo research has found chitosan to be efficacious and safe for use in brain. • Chitosan has similar efficacy and safety compared to other commercial hemostats. • Clinical studies in various clinical (non-neurosurgical) contexts have found chitosan to be safe for human use. Haemorrhage is a major nuance in neurosurgery since blood can distort the surgeon's field of view and increase the risk of post-operative complications. Currently a variety of commercially available haemostats have been approved for use in neurosurgery, but they have caveats to their use in the brain, including, localised tissue compression, neural toxicity, induce immune reaction or form thrombus within the vessel. Thus, there is a need for haemostats that are efficacious and safe for application on brain and spinal tissue. Chitosan is a naturally occurring bio-polymer that is found on the exoskeleton of arthropods and the cell wall of fungi. Chitosan has been shown to accelerate haemostasis through a myriad of physiological pathways. These findings have led to the development of multiple chitosan-based haemostats, for use in peripheral human tissue. Although, clinical data regarding the use of chitosan-based haemostats in the brain is lacking, a range on in vivo studies have proven chitosan to be efficacious and safe in managing neurosurgical bleeds. Similarly, literature comparing chitosan-based haemostats with commercial haemostats used commonly in neurosurgery, have all demonstrated chitosan to be the superior agent. Additionally, clinical trials of chitosan-based haemostat used in peripheral tissue have all demonstrated chitosan to be safe for human use. The marriage of these findings indicates that the safety and superior efficacy of chitosan-based haemostat, makes it a potentially suitable haemostat for use in neurosurgical setting. However, further research pertaining to the clinical use of chitosan-based haemostat within the central nervous system needs to be conducted. [ABSTRACT FROM AUTHOR]

Chronic rhinosinusitis (CRS) has a complex and multifactorial pathogenesis with a heterogeneous inflammatory profile. Proteomic analysis of nasal mucus may enable further understanding of protein abundances and biologic processes present in CRS and its endotypes compared with in healthy patients. Our aim was to determine differences in the nasal mucus proteome of healthy patients and patients with CRS. Nasal mucus was obtained from healthy patients, patients with CRS without nasal polyps (CRSsNP), and patients with CRS with nasal polyps (CRSwNP) before surgery. Gel electrophoresis was performed to fractionate the complex protein extracts before mass spectrometry analysis. Gene set enrichment analysis was performed on differentially expressed proteins. A total of 33 patients were included in this study (12 healthy, 10 with CRSsNP, and 11 with CRSwNP). In all, 1142 proteins were identified in mucus samples from healthy patients, 761 in mucus samples from patients with CRSsNP, and 998 in mucus samples from patients with CRSwNP. Dysfunction in immunologic pathways, reduced cellular signaling, and increased cellular metabolism with associated tissue remodeling pathways were present in patients with CRS compared with in healthy patients. Significant downregulation of mucosal immunity and antioxidant pathways with increased tissue modeling processes may account for the clinical manifestations of CRS. Ultimately, the differing proteome and biologic processes provide further insight into CRS pathogenesis and its endotypes. [ABSTRACT FROM AUTHOR]

• 40% of post-laminectomy patients suffer from Failed Back Surgery syndrome. • Barrier – hydrogels are best bet to prevent adhesion formation post-laminectomy. • Chitogel complexed with the iron chelator Deferiprone is a promising barrier. • Chitogel prevents inflammation and adhesion as seen in a sheep laminectomy model. Spinal laminectomy is a common procedure performed to relieve neural compression in patients suffering from myelopathy or radiculopathy. However, up to 40% of patients suffer from persistent post-operative pain and disability, a condition known as Failed Back Surgery Syndrome (FBSS). Excessive scarring in the surgical bed is implicated as a cause. Hydrogels have been proposed to prevent adhesion formation post-laminectomy; however, their efficacy has not been proven. This study uses Chitogel complexed with the iron chelator Deferiprone (Def) to prevent adhesion formation in a sheep laminectomy model. Fifteen Adult Merino sheep (Ovis Aries, 1–5 yrs old) underwent laminectomy at lumbar levels 1–5 and had hydrated aluminum silicate (kaolin) applied to promote adhesion formation. Subjects were randomised to receive at each laminectomy level no-treatment control, Chitogel, Chitogel with Def at 20 mM or 40 mM or Carboxy-methyl-cellulose and Polyethylene oxide (CMC/PEO) gel. The animals were recovered for 3 months post-surgery, followed by assessment with Magnetic Resonance Imaging (MRI) and histopathology of the spinal tissues for evaluating the presence and extent of adhesions. MRI and Histology assessment indicated that Kaolin induced severe inflammation with adhesion formation. Chitogel with and without 20 mM Def decreased inflammation (p < 0.01) and trended to reduce adhesions (p < 0.1). Chitogel with Def 40 mM was not significantly dis-similar to CMC/PEO and did not reduce inflammation or adhesions compared to no-treatment control. Chitogel in combination with Def 20 mM is safe and effective in decreasing the inflammatory process and may possibly reduce post-operative adhesions following laminectomy. [ABSTRACT FROM AUTHOR]

Pseudomonas aeruginosa (PA) is a bacterial pathogen that frequently displays antibiotic resistance. Its presence within the sinuses of chronic rhinosinusitis sufferers is associated with poorer quality of life. Obligately lytic bacteriophages (phages) are viruses that infect, replicate within, and lyse bacteria, causing bacterial death. The aims of this study were to assess the safety and efficacy of a PA phage cocktail (CT-PA) in a sheep model of rhinosinusitis. The sheep rhinosinusitis model was adapted to simulate PA infection in sheep frontal sinuses. To assess efficacy, after a 7-day biofilm formation period, sheep received twice-daily frontal trephine flushes of CT-PA or saline for 1 week. Biofilm quantitation on frontal sinus mucosa was performed using LIVE/DEAD BacLight staining. To assess safety, sheep received twice-daily frontal trephine flushes of CT-PA or vehicle control for 3 weeks. Blood and fecal samples were collected throughout treatment. Histopathology of frontal sinus, lung, heart, liver, spleen, and kidney tissue was performed. Sinus cilia were visualized using scanning electron microscopy (SEM). The Efficacy arm showed a statistically significant reduction in biofilm biomass with all concentrations of CT-PA tested (P < 0.05). Phage presence in sinuses was maintained for at least 16hours after the final flush. All Safety arm sheep completed 3 weeks of treatment. Phage was detected consistently in feces and sporadically in blood and organ samples. Histology and SEM of tissues revealed no treatment-related damage. In conclusion, CT-PA was able to decrease sinus PA biofilm at concentrations of 108-1010 PFU/mL. No safety concerns were noted. [ABSTRACT FROM AUTHOR]

Non-Tuberculous Mycobacterial Pulmonary Disease (NTM-PD) caused by Mycobacterium abscessus is a frequent complication in patients with cystic fibrosis (CF) that worsens lung function over time. Currently, there is no cure for NTM-PD, hence new therapies are urgently required. Disrupting bacterial iron uptake pathways using gallium-protoporphyrin (IX) (GaPP), a heme analog, has been proposed as a novel antibacterial approach to tackle multi-drug resistant M. abscessus. However, the antibacterial activity of GaPP has been tested only in iron-deficient media, which cannot accurately mirror the potential activity in vivo. Herein, we investigated the potential synergistic activity between GaPP and the iron-chelating agent deferiprone (Def) in regular media against M. abscessus -infected macrophages. The safety of the treatment was assessed in vitro using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in Nuli-1 and THP-1 cell lines. Def-GaPP had synergistic activity against M. abscessus -infected macrophages where 10 mM-12.5 mg/L of Def-GaPP reduced the viability by up to 0.9 log 10. Furthermore, Def-GaPP showed no cytotoxicity to Nuli-1 and THP-1 cell lines at the effective antibacterial concentrations (10 mM-12.5 mg/L) of Def- GaPP. These data encourage future investigation of Def-GaPP as a novel antimicrobial against NTM-PD. [ABSTRACT FROM AUTHOR]

Introduction: Post-operative peridural adhesions increase morbidity after neurosurgical procedures. Aim of this study is to assess safety and efficacy of Chitosan-Dextran (CD) gel as an anti–adhesion agent in a spinal laminectomy sheep model. Methods: Eighteen sheep were used in this study with 6 animals in each treatment arm (namely, CD gel, Gelfoam paste and normal saline control). Posterior lumbar laminectomy was performed in all animals and the dura was exposed intact. Test agents were applied over the exposed dura and the wound was closed in layers. Sheep were euthanized at the end of three months. MRI spine was performed after euthanasia to assess epidural fibrosis. Adhesion in the spinal specimen was assessed by Peel test and histopathology was used to assess safety of the agents. Results: Average scores for the Peel test for CD gel, Gelfoam and normal saline control groups were 1.16 (95% CI, 0.5–1.7), 1.5 (95% CI, 0.6–2.3) and 3 (95% CI, 2.1–3.8) respectively. There was significant reduction in adhesions between treatment and normal saline treated groups ( p = 0.0292), with no difference between Gelfoam and CD gel groups ( p = 0.56). Average scores on MRI for CD gel, Gelfoam and normal saline groups were 1.4 (95% CI, 0.9–1.8), 1.5 (95% CI, 1.2–1.8) and 1.6 (95% CI, 1.3–1.8) respectively, with no significant difference in fibrosis amongst ( p = 0.2992). Histopathology did not show any adverse effects. Conclusion: CD gel is an effective agent to reduce epidural adhesions with a good safety profile in neural tissue. [ABSTRACT FROM AUTHOR]

[Display omitted] Chronic rhinosinusitis (CRS) is a persistent inflammation of the sinus mucosa associated with dysfunction of the sinuses' natural defense mechanism and induction of different inflammatory clusters. Severe recalcitrant CRS is unresponsive to medical and surgical interventions and often has Staphylococcus aureus –dominant mucosal biofilms. This study aimed to characterize in vitro grown S aureus biofilm properties in relation to inflammation and CRS severity. The spatial pattern of inflammatory cells in patients' sinonasal tissue was also examined. S aureus isolated from the nasal swabs of patients with CRS with nasal polyps (CRSwNP), those with CRS without nasal polyps, and controls (n = 72) were grown into biofilm in vitro , and their metabolic activity, biomass, colony-forming units, and exoprotein production were quantified. S aureus virulence genes were evaluated using whole-genome sequencing. Patients' matched sinonasal tissue blocks (n = 57) were analyzed using Opal multiplex immunostaining, and their disease severity was determined using the Lund-Mackay computed tomography score. Correlations among S aureus biofilm properties, the frequency and localization of key immune cells in corresponding sinonasal mucosa, and the disease severity were investigated. Increased infiltration of CD3+, CD68+, CD20+, and CD138+ cells was observed in tissue of patients with CRSwNP compared to tissue from controls. CD3+, CD138+, and MBP+ cells diffused deeper into the tissue in CRSwNP but clustered close to the epithelium in controls. This study also found CRSwNP–derived S aureus biofilms showed thicker biomass, higher colony-forming units, and higher exoprotein production than those from controls did (P <.05). S aureus biofilm properties, inflammatory cell numbers, and CRS severity scores were positively correlated. These findings support the notion of an aberrant immunolocalization of key immune cells in CRSwNP with a critical role of S aureus biofilms in CRS etiopathogenesis. [ABSTRACT FROM AUTHOR]

The burden of drug resistance emerges in the wake of chronic and repeated antibiotic use. This underpins the importance of discovering alternatives to current antibiotic regimens. In chronic rhinosinusitis (CRS), topical therapy such as nasal douches and steroid sprays is the mainstay of treatment. However, bacterial sinusitis such as those with Staphylococcus aureus biofilm infection point to more recalcitrant CRS subtypes, focusing research efforts into topical antimicrobial therapies. In the sinuses, both local mucosal and systemic effects must be considered in designing any new topical medication. Nitric oxide (NO), an endogenous antimicrobial agent, is found at extremely low levels in CRS sinuses and high levels in healthy sinuses. As a novel treatment modality, we have designed a liposomal formulation of an NO donor (LFNO) using isosorbide mononitrate, as a topical sinus wash in a sheep model of S. aureus biofilm rhinosinusitis. Heart rate (HR), blood pressure, mean arterial pressure (MAP), and histologic and ciliary analyses were assessed in the safety component. Efficacy was assessed by quantifying biofilm biomass post-treatment. LFNO-treated sheep had lesser inflammation (P = 0.02), and comparable ciliary preservation (P = 0.86) than the control group. A transient increase in HR and decrease in MAP were observed in the LFNO group (P < 0.05), but this was not accompanied by observable side effects. LFNO sheep had significantly lower biofilm biomass vs controls (P = 0.044). Our findings demonstrate the localized and systemic safety of LFNO in an animal model despite using high NO concentrations, thus warranting further investigation for its possible therapeutic role in CRS. [ABSTRACT FROM AUTHOR]

Sentinel lymph node biopsy in cancers of the head and neck offers demonstrated clinical and diagnostic value, but adoption is limited by concerns about the detrimental consequence to survival of false negative results in a highly curable setting. The aim of this study was to demonstrate potential to overcome this via application of a novel mannose-labeled magnetic iron oxide tracer. In a large animal model, preoperative imaging and intraoperative magnetometer detection were used to identify magnetic lymph nodes. Iron quantification mapped the distribution of tracer within lymphatic levels. Over a 4-week test period, uptake of magnetic tracer in lymph nodes increased in a linear-like fashion, with a substantial percentage of accumulated iron (83%) being retained in the sentinel node. This result indicates a high affinity of mannose-labeled particles to the sentinel node, while providing a means for the magnetometer probe to indicate node status based on intraoperative signal. A mannose-labeled SPION, "FerroTrace" was developed with a maghemite iron oxide core and a stabilizing-polymer and a macrophage-targeting mannose-polymer attached. In a large animal model, preoperative imaging and intraoperative magnetometer detection identified magnetic lymph nodes. Iron quantification mapped tracer distribution within lymphatic levels over a 4-week test period. Magnetic tracer in lymph nodes increased in a linear-like fashion, with a substantial percentage of accumulated iron (83%) retained in sentinel nodes indicating high affinity of mannose-labeled particles to the sentinel node, while providing a means for the magnetometer probe to indicate node status based on intraoperative signal. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: There is little scientific evidence to support the current practice of using oral glucocorticosteroids and antibiotics to treat patients with chronic rhinosinusitis and nasal polyps. Objective: We evaluated the effects of oral glucocorticoids and doxycycline on symptoms and objective clinical and biological parameters in patients with chronic rhinosinusitis and nasal polyps. Methods: In a double-blind, placebo-controlled, multicenter trial, we randomly assigned 47 participants with bilateral nasal polyps to receive either methylprednisolone in decreasing doses (32–8 mg once daily), doxycycline (200 mg on the first day, followed by 100 mg once daily), or placebo for 20 days. Participants were followed for 12 weeks. Patients were assessed for nasal peak inspiratory flow and symptoms and by nasal endoscopy. Markers of inflammation such as eosinophilic cationic protein (ECP), IL-5, myeloperoxidase, matrix metalloproteinase 9, and IgE were measured in nasal secretions. Concentrations of eosinophils, ECP, and soluble IL-5 receptor α were measured in peripheral blood samples. Results: Methylprednisolone and doxycycline each significantly decreased nasal polyp size compared with placebo. The effect of methylprednisolone was maximal at week 3 and lasted until week 8, whereas the effect of doxycycline was moderate but present for 12 weeks. Methylprednisolone significantly reduced levels of ECP, IL-5, and IgE in nasal secretions, whereas doxycycline significantly reduced levels of myeloperoxidase, ECP, and matrix metalloproteinase 9 in nasal secretions. Conclusion: This is the first double-blind, placebo-controlled study to show a significant effect of oral methylprednisolone and doxycycline on size of nasal polyps, nasal symptoms, and mucosal and systemic markers of inflammation. [Copyright &y& Elsevier]

The present study describes and compares functional properties of Nuli-1 cells and primary human nasal epithelial cells (HNEC) including TLR expression and function. Differences in gene expression were identified for non-TLR genes that play a role in TLR response pathways. However, experiments comparing TLR gene expression for both Nuli-1 cells and HNECs indicated conserved expression in both cell types. Stimulation of the two cell types resulted in a conserved response to TLR3 agonists, but in differences in response to agonists for TLR5 and TLR6/2. HNECs were much more susceptible to infection with Staphylococcus aureus than NuLi-1 cells. Furthermore, when cultured at air-liquid interface (ALI), NuLi-1 cells possessed much lower trans-epithelial resistance than primary HNEC and did not exhibit maintenance of cell morphology or mucous production which was observed in HNECs. Nor did they produce the characteristic interconnecting pattern of tight junction complexes at the apicolateral margin of adjacent cells. Caution should therefore be exercised when selecting cell lines for immunological studies and a thorough screen of properties relevant to the study should always be carried out prior to commencement. [ABSTRACT FROM AUTHOR]

[Display omitted] • TMA attenuates transepithelial electrical resistance and increases paracellular permeability. • ZO-1 and claudin-1 are disrupted by TMA in a dose-dependent manner. • Trimellitic anhydride shows cytotoxicity only after prolonged incubation. Trimellitic anhydride (TMA) is a chemical agent classified as a low molecular weight (LMW) agent causing occupational rhinitis (OR) or asthma. Although TMA is recognized as a respiratory sensitizer, the direct and non-immunologic effects of TMA remain unclear. Air- liquid interface (ALI) cultured human nasal epithelial cells (HNECs) derived from control subjects were treated with TMA, followed by measurement of the transepithelial electrical resistance (TEER), paracellular permeability of fluorescein isothiocyanate (FITC)-dextran and immunofluorescence of tight junction proteins claudin-1 and zonula occludens-1 (ZO-1). The cytotoxicity of TMA was evaluated by lactate dehydrogenase (LDH) assay. TMA at concentrations of 2 and 4 mg/mL significantly reduced the TEER within 10 min (p = 0.0177 on 2 mg/mL; p < 0.0001 on 4 mg/mL). The paracellular permeability of FITC-dextran was significantly increased upon challenge with 4 mg/mL TMA for 3 h (p = 0.0088) and 6 h (p = 0.0004). TMA treatment induced a reduction in the fluorescence intensity of claudin-1 and ZO-1 in a dose-dependent manner. LDH assay revealed 4 mg/mL TMA induced cytotoxicity only after 6 h incubation, while 1 or 2 mg/mL TMA caused no cytotoxicity. Our results suggest that TMA has a potential to penetrate the epithelial barrier by disrupting claudin-1 and ZO-1, indicating an important role for sensitization and OR development. [ABSTRACT FROM AUTHOR]

Objective: Recently, depleted tissue zinc levels were found in nasal mucosa from patients with chronic rhinosinusitis (CRS) in correlation with tissue eosinophilia, however, no clinical biomarkers for tissue zinc levels have been identified. Metallothionein-3 (MT3) is an intracellular zinc chelator and previous data showed MT3 mRNA levels to be reduced in CRS patients with nasal polyps (CRSwNP). In this study, we examined the correlation between MT3 expression and zinc levels in nasal mucosa and primary human nasal epithelial cells (HNECs) to investigate whether MT3 could be a clinical biomarker for tissue zinc levels.Method: Tissue was harvested from 36 patients and mounted on tissue micro-array (TMA) slides. MT3 expression and tissue zinc fluorescence intensity were measured at different areas within the mucosa (surface epithelium and lamina propria) and compared between controls, CRSwNP and CRS without nasal polyps (CRSsNP) patients. MT3 mRNA and protein expression were examined in zinc-depleted HNECs by qPCR and immunofluorescence microscopy.Results: MT3 expression in CRSwNP was significantly decreased in both surface epithelium (p<0.001 to controls) and lamina propria (p = 0.0491 to controls). There was a significant positive correlation between tissue zinc levels and MT3 expression in nasal mucosa (r = 0.45, p = 0.007). In zinc-deplete HNECs, MT3 expression was significantly decreased at mRNA (p = 0.02) and protein level (p<0.01). There was a significant positive correlation between tissue zinc levels and MT3 expression within individual HNECs (r = 0.59, p<0.001).Conclusions: MT3 expression reflects intramucosal zinc levels in both nasal mucosa and HNECs indicating MT3 could be used as a clinical biomarker for monitoring intracellular zinc levels in the nasal mucosa. [ABSTRACT FROM AUTHOR]

Chronic rhinosinusitis (CRS) is a persistent inflammation of the sinus mucosa. Recalcitrant CRS patients are unresponsive to medical and surgical interventions and often present with nasal polyps, tissue eosinophilia, and Staphylococcus aureus dominant mucosal biofilms. However, S. aureus sinonasal mucosal colonisation occurs in the absence of inflammation, questioning the role of S. aureus in CRS pathogenesis. Here, we aimed to investigate the relationship between S. aureus biofilm metabolic activity and virulence genes, innate immune cells, and disease severity in CRS. Biospecimens, including sinonasal tissue and nasal swabs, and clinical datasets, including disease severity scores, were obtained from CRS patients and non-CRS controls. S. aureus isolates were grown into biofilms in vitro , characterised, and sequenced. The patients' innate immune response was evaluated using flow cytometry. S. aureus was isolated in 6/19 (31.58%) controls and 23/53 (43.40%) CRS patients of 72 recruited patients. We found increased S. aureus biofilm metabolic activity in relation to increased eosinophil cell frequencies and disease severity in recalcitrant CRS cases. Mast cell frequencies were higher in tissue samples of patients carrying S. aureus harbouring lukF.PV , sea, and fnbB genes. Patients with S. aureus harbouring lukF.PV and sdrE genes had more severe disease. This offers insights into the pathophysiology of CRS and could lead to the development of more targeted therapies. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] Chronic rhinosinusitis (CRS) impacts patients' quality of life and healthcare costs. Traditional methods of drug delivery, such as nasal sprays and irrigation, have limited effectiveness. Acoustic Drug Delivery (ADD) using a nebulizer offers targeted delivery of drug to the sinuses, which may improve the treatment of CRS. This review examines the influence of aerosol particle characteristics, aero-acoustic parameters, inlet flow conditions, and acoustic waves on sinus drug delivery. Key findings reveal that smaller particles improve the ADD efficiency, whereas larger sizes or increased density impair it. The oscillation amplitude of the air plug in the ostium is crucial for the ADD efficiency. Introducing acoustic waves at the NC-sinus system's resonance frequency improves aerosol deposition within sinuses. Future research should address advanced models, optimizing particle characteristics, investigating novel acoustic waveforms, incorporating patient-specific anatomy, and evaluating long-term safety and efficacy. Tackling these challenges, ADD could offer more effective and targeted treatments for sinus-related conditions such as CRS. [ABSTRACT FROM AUTHOR]

Chronic rhinosinusitis (CRS) is a common sinonasal condition that debilitates quality of life. Nasal sprays are inefficient for targeting the sinuses because of the highly inertial atomised droplets. This study evaluated sinus drug delivery via a nebuliser in a human nasal cavity using Computational Fluid Dynamics (CFD) simulations of different breathing conditions. The nebuliser was quantified through high-speed imaging of the spray plume and average velocity, while laser diffraction was used for droplet size distributions. A CT scan was acquired of a 75-year-old male with a confirmed diagnosis of CRS, and airway segmentation was performed to extract the nasal cavity and sinuses. Virtual surgery was then performed on the computational model. Two nozzle designs for the nebuliser under normal breathing, slow exhalation, and breath hold were investigated. The results demonstrated that drug delivery with a fully blocked nostril with a breath hold notably improved deposition targeting the maxillary sinuses and ethmoid sinuses, while using a nozzle that allowed co-flow of air was recommended for targeting the frontal and sphenoid sinuses. • A breath-hold following inhalation with nebulised droplets <15 μm improved ethmoid sinus deposition. • An occluded nostril with 15 μm droplets improved maxillary sinus deposition. • A fully blocked nostril with a breath hold improved deposition in the maxillary sinuses and ethmoid sinuses. • A partially blocked nostril improved deposition in the frontal and sphenoid sinuses. [ABSTRACT FROM AUTHOR]

Corynebacterium accolens strains are increasingly recognized as beneficial bacteria that can confer a health benefit on the host. In the current study, the probiotic potential of three C. accolens strains, C779, C781 and C787 derived from a healthy human nasal cavity were investigated. These strains were examined for their adhesion to HNECs, competition with Staphylococcus aureus for adhesion, toxicity, induction of IL-6, antibiotic susceptibility and the presence of antibiotic resistance and virulence genes. Furthermore, the safety and efficacy of strains were evaluated in vivo using Caenorhabditis elegans. The adhesion capacity of C. accolens to HNECs was strain-dependent. Highest adhesion was observed for strain C781. None of the C. accolens strains tested caused cell lysis. All strains were able to outcompete S. aureus for cell adhesion and caused a significant decrease of IL-6 production by HNECs co-exposed to S. aureus when compared to the control groups. All strains were sensitive or showed intermediate sensitivity to 10 different antibiotics. Whole Genome Sequence analysis showed C. accolens C781 and C787 did not possess antibiotic resistance genes whereas strain C779 harboured 5 genes associated with resistance to Aminoglycoside, Chloramphenicol and Erythromycin. In addition, no virulence genes were detected in any of the 3 strains. Moreover, the tested strains had no detrimental effect on worm survival and induced protection from S. aureus -mediated infection. Taken all together, C. accolens strains, C781 and C787 displayed probiotic potential and hold promise for use in clinical applications for combating dysbiosis in chronic rhinosinusitis. [ABSTRACT FROM AUTHOR]

Evaluating the safety of previously fabricated and effective green synthetized colloidal silver (GSCS) on the mucosal barrier structure and function is essential prior to conduct human trials. The GSCS was applied to primary human nasal epithelial cells (HNECs) grown in an air-liquid interface (ALI) culture. Epithelial barrier integrity was evaluated by measuring the transepithelial electrical resistance (TEER) and fluorescein isothiocyanate (FITC)-dextran paracellular permeability. Ciliary beat frequency (CBF) was quantified. Effects of the GSCS on cell viability and inflammation were examined through lactate dehydrogenase, the 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide viability assay and interleukin 6 (IL-6) enzyme linked immunosorbent assay. The localization and transportation of GSCS within HNECs and their HNEC-ALI cultures was assessed by transmission electron microscopy and inductively coupled plasma-mass-spectrometry, respectively. Application of GSCS to HNECs-ALI cultures for up to 2 h caused a significant reduction in the TEER values, however, it did not drop within the first 10 and 20 min for CRS and non-CRS control HNECs. The paracellular permeability, cell viability, IL-6 secretion and CBF remained unchanged. No GSCS was observed within or transported across HNECs. In conclusion, application of GSCS to HNECs is devoid of toxic effects. [ABSTRACT FROM AUTHOR]

[Display omitted] Acoustic drug delivery (ADD) is an innovative method for drug delivery to the nose and paranasal sinuses and can be used to treat chronic rhinosinusitis (CRS). The underlying mechanism of ADD is based on the oscillatory exchange of air between the nasal cavity (NC) and the maxillary sinus (MS) through the ostium, which assists with the transfer of the drug particles from the NC to the sinuses. This study aims to examine the efficacy of ADD for drug delivery to the MS using an acoustic wave applied to nebulised aerosols entering the nostril. Here, the effect of acoustic frequency, amplitude, and nebulisation flowrate on the efficiency of ADD to the MS is investigated experimentally. A computational fluid dynamics model was also developed to understand the deposition and transport patterns of the aerosols. The results showed that superimposing an acoustic frequency of 328 Hz, which is the resonance frequency of the selected 3D printed model of the NC-MS combination, on the nebulised aerosols could improve the efficiency of the drug delivery to the MS by 75-fold compared with non-acoustic drug delivery case (p < 0.0001). The experimental data also shows that an increase in the amplitude of excitation, increases the concentration of aerosol deposition in the MS significantly; however, it reaches to a plateau at a sound pressure level of 120 dB re 20 µPa. [ABSTRACT FROM AUTHOR]