Publications by authors named "Peter-John Wormald"

307 Publications

Chronic Rhinosinusitis, Biofilm and Secreted Products, Inflammatory Responses, and Disease Severity.

Biomedicines 2022 Jun 9;10(6). Epub 2022 Jun 9.

Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide 5000, Australia.

Chronic rhinosinusitis (CRS) is a persistent inflammation of the nasal cavity and paranasal sinuses associated with tissue remodelling, dysfunction of the sinuses' natural defence mechanisms, and induction of different inflammatory clusters. The etiopathogenesis of CRS remains elusive, and both environmental factors, such as bacterial biofilms and the host's general condition, are thought to play a role. Bacterial biofilms have significant clinical relevance due to their potential to cause resistance to antimicrobial therapy and host defenses. Despite substantial medical advances, some CRS patients suffer from recalcitrant disease that is unresponsive to medical and surgical treatments. Those patients often have nasal polyps with tissue eosinophilia, -dominant mucosal biofilm, comorbid asthma, and a severely compromised quality of life. This review aims to summarise the contemporary knowledge of inflammatory cells/pathways in CRS, the role of bacterial biofilm, and their impact on the severity of the disease. Here, an emphasis is placed on biofilm and its secreted products. A better understanding of these factors might offer important diagnostic and therapeutic perceptions for recalcitrant disease.
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http://dx.doi.org/10.3390/biomedicines10061362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9220248PMC
June 2022

The anatomy of the foramina and efferent nerve fibers from the pterygopalatine ganglion in posterolateral nasal wall.

Laryngoscope Investig Otolaryngol 2022 Jun 20;7(3):679-683. Epub 2022 May 20.

Department of Surgery-Otolaryngology, Head and Neck Surgery University of Adelaide Adelaide South Australia Australia.

Background: The advance of endoscopic surgery has enabled selective section of the postganglionic nerve branches from pterygopalatine ganglion (PPG) as a modification of the vidian neurectomy. Recent microanatomic studies have suggested that the nasal mucosa is also innervated by multiple efferent rami associated with the sphenopalatine artery (SPA) in the procedure "posterior nasal neurectomy." This anatomic cadaveric study aims to identify all postganglionic nerve fibers in the lateral nasal wall which should inform future surgical procedures aimed at interrupting these nerve fibers.

Methods: Two cadaver heads, with a total of three individual sides, were dissected. All neurovascular structures penetrating the vertical plate of palatine bone were carefully identified following meticulous removal of the overlying mucosa layers. The efferent nerve fibers were identified and dissected back to their origin-the PPG or greater palatine nerve.

Results: Several foramina with efferent PPG nerves were identified on the vertical plate of the palatine bone and medial pterygoid plate. The superior, middle, and inferior turbinates (IT) were innervated by efferent nerves from the PPG via the anterior region of the SPA. The IT was innervated from nerves originating from behind the SPA through bony foramina. The lateral wall of inferior meatus was innervated by efferent nerves that originated from greater palatine nerve and pharyngeal nerve.

Conclusion: This study demonstrated the anatomical positions of the postganglionic nerves that innervate the lateral nasal wall. These nerves are located anterior to the SPA as well as posterior to the SPA, where they penetrate the palatine bone.Level of evidence: NA.
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http://dx.doi.org/10.1002/lio2.808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9194985PMC
June 2022

APTC-C-SA01: A Novel Bacteriophage Cocktail Targeting and MRSA Biofilms.

Int J Mol Sci 2022 May 30;23(11). Epub 2022 May 30.

Department of Surgery-Otolaryngology Head and Neck Surgery, Basil Hetzel Institute for Translational Health Research, Central Adelaide Local Health Network, Woodville, SA 5011, Australia.

The high infection and mortality rate of methicillin-resistant (MRSA) necessitates the urgent development of new treatment strategies. Bacteriophages (phages) have several advantages compared to antibiotics for the treatment of multi-drug-resistant bacterial infections, and thus provide a promising alternative to antibiotics. Here, phages were isolated from patients and environmental sources. Phages were characterized for stability, morphology and genomic sequence and their bactericidal activity against the biofilm form of methicillin-susceptible (MSSA) and MRSA was investigated. Four phages were isolated and tested against 51 MSSA and MRSA clinical isolates and reference strains. The phages had a broad host range of 82-94% individually and of >98% when combined and could significantly reduce the viability of biofilms. The phages had a latent period of ≤20 min and burst size of >11 plaque forming units (PFU)/infected cell. Transmission electron microscopy (TEM) identified phages belonging to the family of . Genomic sequencing indicated the lytic nature of all four phages, with no identified resistance or virulence genes. The 4 phages showed a high complementarity with 49/51 strains (96%) sensitive to at least 2/4 phages tested. Furthermore, the frequency of bacteriophage insensitive mutant (BIM) generation was lower when the phages were combined into the phage cocktail APTC-C-SA01 than for bacteria exposed to each of the phages alone. In conclusion, APTC-C-SA01, containing four lytic phages has the potential for further development as a treatment against MSSA and MRSA infections.
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http://dx.doi.org/10.3390/ijms23116116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9181636PMC
May 2022

Prophage: a crucial catalyst in infectious disease modulation.

Lancet Microbe 2022 Mar 25;3(3):e162-e163. Epub 2022 Jan 25.

Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia; Department of Surgery-Otolaryngology Head and Neck Surgery, The Basil Hetzel Institute for Translational Health Research, Central Adelaide Local Health Network, Woodville South, SA 5011, Australia. Electronic address:

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http://dx.doi.org/10.1016/S2666-5247(21)00354-2DOI Listing
March 2022

Efficacy and Safety of Novel Beta-Chitin Patches as Haemostat in Rat Vascular and Neurosurgical Model.

Front Surg 2022 8;9:830364. Epub 2022 Apr 8.

Department of Surgery-Otorhinolaryngology, Head and Neck Surgery, University of Adelaide, Adelaide, SA, Australia.

Background: Intraoperative hemorrhage is a major cause of poor post-operative outcome. Beta-chitin patch has previously been found to be an effective haemostat, but whether modifying the patch can improve its efficacy and safety, remains unknown. In this study, beta-chitin patches were modified using polyethylene oxide, Pluronic-F127 (Chi/F127), calcium (Chi/20%Ca), increased thickness (Chi/Thick) or polyphosphate (Chi/PP).

Objective: Using rat (Wistar Albino; 8-10 weeks old) vascular and neurosurgical models, this project investigated and compared the efficacy and safety of beta-chitin patches with gauze, Surgicel and FloSeal.

Methods: Ninety rats underwent a standardized femoral artery injury and were randomized to receive either beta-chitin patches, gauze, Surgicel or FloSeal. The bleeding time and total blood loss was measured. For the neurosurgical model, forty-four rats underwent a standardized cortical injury and randomization to a treatment group. Following a 48 h recovery period, their brains were collected for histopathological examination.

Results: The mean bleeding time with Chitin (120.8 s) and Chi/PP (117.3 s) was ~60 s lower than Chi/F127, Chi/20%Ca and Chi/Thick ( < 0.05). Chitin and Chi/PP had a significantly lower bleeding time than FloSeal (174.2 s) ( < 0.05), but not Surgicel (172.7 s). Gauze (400 s) had a significantly higher bleeding time compared to all other groups ( < 0.05). There were no significant differences in the total blood loss between the groups. Histopathological examination of brains found no adverse inflammatory reaction to any of the haemostatic compounds.

Conclusion: Chi/PP had superior haemostatic efficacy compared to Surgicel and FloSeal, but not compared to non-modified beta-chitin patch. All of the haemostats were equally safe.
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http://dx.doi.org/10.3389/fsurg.2022.830364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9023757PMC
April 2022

Characterization of human nasal organoids from chronic rhinosinusitis patients.

Biol Open 2022 Apr 22. Epub 2022 Apr 22.

Department of Surgery-Otolaryngology, Head and Neck Surgery, Central Adelaide Local Health Network (Basil Hetzel Institute), The Queen Elizabeth Hospital and The University of Adelaide, Adelaide, Australia.

Patient-derived organoids grown in three-dimensional cultures provide an excellent platform for phenotypic high-throughput screening and drug response research. Organoid technology has been applied to study stem cell biology and various human pathologies. This study investigates the characteristics and cellular morphology of organoids derived from primary human nasal epithelial cells (HNECs) of chronic rhinosinusitis (CRS) patients. Nasal organoids were cultured up to 20 days and morphological, cell composition, and functional parameters were measured by immunofluorescence, RT-qPCR, western-blot and FACS analysis. The results showed that nasal organoids expressed the stem cell marker Leucine Rich Repeat Containing G Protein-Coupled Receptor 5 (LGR5), and markers for apical junction genes, goblet cells and ciliated cells. Moreover, we were able to regrow and expand the nasal organoids well after freezing and thawing. This study promise an effective and feasible method for development of human nasal organoids, suitable for the phenotypic high-throughput screening and drug response research.
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http://dx.doi.org/10.1242/bio.059267DOI Listing
April 2022

Der p 1 Disrupts the Epithelial Barrier and Induces IL-6 Production in Patients With House Dust Mite Allergic Rhinitis.

Front Allergy 2021 3;2:692049. Epub 2021 Aug 3.

Department of Surgery-Otolaryngology, Head and Neck Surgery, University of Adelaide, Adelaide, SA, Australia.

1/2 (Der p 1/Der p 2) are regarded as important allergens of house dust mite (HDM). However, the effect of both products on the epithelial barrier and immune response of patients with and without HDM allergic rhinitis (AR) remains unclear. Air-liquid interface (ALI) cultured human nasal epithelial cells (HNECs) derived from control subjects (non-AR) ( = 9) and HDM-AR patients ( = 9) were treated with Der P 1 and Der P 2, followed by testing the transepithelial electrical resistance (TEER), paracellular permeability of fluorescein isothiocyanate (FITC)-dextrans and immunofluorescence of claudin-1 and ZO-1. Interleukin-6 (IL-6) production was evaluated by ELISA. Der p 1 reduced TEER significantly in a transient and dose-dependent manner in HNEC-ALI cultures from HDM-AR and non-AR patients, whilst the paracellular permeability was not affected. TEER was significantly reduced by Der p 1 at the 10-min time point in HDM-AR patients compared to non-AR patients ( = 0.0259). Compared to no-treatment control, in HNECs derived from HDM-AR patients, Der p 1 significantly cleaved claudin-1 after 30 min exposure (72.7 ± 9.5 % in non-AR group, 39.9 ± 7.1 % in HDM-AR group, = 0.0286) and induced IL-6 secretion ( = 0.0271). Our results suggest that patients with HDM-AR are more sensitive to Der p 1 than non-AR patients with increased effects of Der p1 on the mucosal barrier and induction of inflammation, indicating an important role for Der p1 in sensitization and HDM-AR development.
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http://dx.doi.org/10.3389/falgy.2021.692049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8974687PMC
August 2021

In vitro safety and anti-bacterial efficacy assessment of acriflavine.

Allergy 2022 06 31;77(6):1917-1920. Epub 2022 Mar 31.

Department of Otolaryngology Head and Neck Surgery, University of Adelaide, Adelaide, SA, Australia.

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http://dx.doi.org/10.1111/all.15289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9311691PMC
June 2022

Chitogel following endoscopic sinus surgery promotes a healthy microbiome and reduces postoperative infections.

Int Forum Allergy Rhinol 2022 Mar 23. Epub 2022 Mar 23.

Department of Surgery - Otolaryngology, Head and Neck Surgery, University of Adelaide, South Australia, Australia.

Background: Postoperative infections following endoscopic sinus surgery (ESS) impair wound healing and lead to poor outcomes. The aim of this study is to assess the effectiveness of Chitogel to reduce postoperative infections and restore a healthy microbiome following ESS.

Methods: In this double-blinded randomized control trial, 25 patients undergoing ESS were prospectively recruited. At the end of surgery, patients were randomized to receive Chitogel to one side of the sinuses (allowing the other side to serve as control). Patients underwent routine follow-up with nasoendoscopies performed at 2, 6, and 12 weeks postoperatively. Sinus ostial measurements, microbiology, and microbiome swabs from bilateral sides were collected intraoperatively and at 12 weeks postoperatively. Additional swabs were collected if infection was present.

Results: Improved endoscopic appearance of the sinuses (p = 0.03) and ostial patency were noted on the Chitogel side compared with control at 12 weeks (p < 0.001). A significant decrease in infections on the Chitogel side (12.0%) compared with control (52.0%) (p = 0.005) was evident. Following the use of Chitogel, there was a significant increase in the combined relative abundance of commensals Corynebacterium and Cutibacterium (Propionibacterium) from 30.15% at baseline to 46.62% at 12 weeks compared with control (47.18% to 40.79%) (p.adj = 0.01).

Conclusion: Chitogel significantly improved both the nasoendoscopic appearance of the sinuses and sinus ostial patency at 12 weeks postoperatively. Chitogel used following ESS helps restore an improved microbiome resulting in an increase in the relative abundance of commensals Corynebacterium and Cutibacterium (Propionibacterium). A significant decrease in postoperative infections was noted following use of Chitogel.
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http://dx.doi.org/10.1002/alr.23001DOI Listing
March 2022

Preclinical evaluation of a mannose-labeled magnetic tracer for enhanced sentinel lymph node retention in the head and neck.

Nanomedicine 2022 06 10;42:102546. Epub 2022 Mar 10.

Future Industries Institute, University of South Australia, Mawson Lakes, SA, Australia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.nano.2022.102546DOI Listing
June 2022

APTC-EC-2A: A Lytic Phage Targeting Multidrug Resistant Planktonic Cells and Biofilms.

Microorganisms 2022 Jan 4;10(1). Epub 2022 Jan 4.

Department of Health and Medical Sciences-Surgery, The University of Adelaide, Adelaide 5000, Australia.

() are common bacteria that colonize the human and animal gastrointestinal tract, where they help maintain a balanced microbiome. However, some strains are pathogenic and can cause serious infectious diseases and life-threatening complications. Due to the overuse of antibiotics and limited development of novel antibiotics, the emergence of antibiotic-resistant strains has threatened modern medicine, whereby common infections can become lethal. Phage therapy has once again attracted interest in recent years as an alternative treatment option to antibiotics for severe infections with antibiotic-resistant strains. The aim of this study was to isolate and characterize phage against multi-drug resistant isolated from clinical samples and hospital wastewater. For phage isolation, wastewater samples were collected from The Queen Elizabeth Hospital (Adelaide, SA, Australia) followed by phage enrichment as required. Microbiological assays, electron microscopy and genomic sequencing were carried out to characterize the phage. From the 10 isolated phages, phage APTC-EC-2A was the most promising and could lyse 6/7 clinical isolates. APTC-EC-2A was stable at a broad pH range (3-11) and could lyse the host at temperatures ranging between 30-50 °C. Furthermore, APTC-EC-2A could kill in planktonic and biofilm form. Electron microscopy and genomic sequencing indicated the phage to be from the family and of lytic nature. In conclusion, the newly isolated phage APTC-EC-2A has the desired properties that support its potential for development as a therapeutic agent against therapy refractory infections.
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http://dx.doi.org/10.3390/microorganisms10010102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8779906PMC
January 2022

Prophages encoding human immune evasion cluster genes are enriched in isolated from chronic rhinosinusitis patients with nasal polyps.

Microb Genom 2021 12;7(12)

Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia.

Prophages affect bacterial fitness on multiple levels. These include bacterial infectivity, toxin secretion, virulence regulation, surface modification, immune stimulation and evasion and microbiome competition. Lysogenic conversion arms bacteria with novel accessory functions thereby increasing bacterial fitness, host adaptation and persistence, and antibiotic resistance. These properties allow the bacteria to occupy a niche long term and can contribute to chronic infections and inflammation such as chronic rhinosinusitis (CRS). In this study, we aimed to identify and characterize prophages present in from patients suffering from CRS in relation to CRS disease phenotype and severity. Prophage regions were identified using PHASTER. Various tools like ResFinder and VF Analyzer were used to detect virulence genes and antibiotic resistance genes respectively. Progressive MAUVE and maximum likelihood were used for multiple sequence alignment and phylogenetics of prophages respectively. Disease severity of CRS patients was measured using computed tomography Lund-Mackay scores. Fifty-eight clinical isolates (CIs) were obtained from 28 CRS patients without nasal polyp (CRSsNP) and 30 CRS patients with nasal polyp (CRSwNP). All CIs carried at least one prophage (average=3.6) and prophages contributed up to 7.7 % of the bacterial genome. Phage integrase genes were found in 55/58 (~95 %) strains and 97/211 (~46 %) prophages. Prophages belonging to Sa3int integrase group (phiNM3, JS01, phiN315) (39/97, 40%) and Sa2int (phi2958PVL) (14/97, 14%) were the most prevalent prophages and harboured multiple virulence genes such as E/D, . Intact prophages were more frequently identified in CRSwNP than in CRSsNP (=0.0021). Intact prophages belonging to the Sa3int group were more frequent in CRSwNP than in CRSsNP (=0.0008) and intact phiNM3 were exclusively found in CRSwNP patients (=0.007). Our results expand the knowledge of prophages in isolated from CRS patients and their possible role in disease development. These findings provide a platform for future investigations into potential tripartite associations between bacteria-prophage-human immune system, evolution and CRS disease pathophysiology.
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http://dx.doi.org/10.1099/mgen.0.000726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8767322PMC
December 2021

In vitro and in vivo evaluation of probiotic properties of Corynebacterium accolens isolated from the human nasal cavity.

Microbiol Res 2021 Nov 23;255:126927. Epub 2021 Nov 23.

Department of Surgery-Otolaryngology, Head and Neck Surgery, The University of Adelaide, Basil Hetzel Institute for Translational Health Research, Central Adelaide Local Health Network, Woodville, SA, Australia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.micres.2021.126927DOI Listing
November 2021

The potential of chitosan-based haemostats for use in neurosurgical setting - Literature review.

J Clin Neurosci 2021 Dec 25;94:128-134. Epub 2021 Oct 25.

Department of Surgery-Otorhinolaryngology, Head and Neck Surgery, University of Adelaide, Adelaide, Australia.

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.
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http://dx.doi.org/10.1016/j.jocn.2021.10.018DOI Listing
December 2021

Silver nanoparticles as a bioadjuvant of antibiotics against biofilm-mediated infections with methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa in chronic rhinosinusitis patients.

Pathology 2022 Jun 26;54(4):453-459. Epub 2021 Nov 26.

Department of Surgery-Otolaryngology Head and Neck Surgery, Basil Hetzel Institute for Translational Health Research, Central Adelaide Local Health Network, Woodville South, SA, Australia; The University of Adelaide, Adelaide, SA, Australia. Electronic address:

Infectious diseases caused by antibiotic-resistant bacteria in planktonic and biofilm form are difficult to treat with conventional antibiotics. Silver nanoparticles (Ag NPs) can be used as alternatives to antibiotics and can alter the susceptibility of bacteria to antibiotics. Here, the antibacterial properties of 16 different antibiotics and Ag NPs, alone and in combination, were tested against clinical isolates of Pseudomonas aeruginosa (n=3), Staphylococcus aureus (n=3) and methicillin-resistant Staphylococcus aureus (MRSA) (n=2) isolated from chronic rhinosinusitis (CRS) patients. The microdilution method and resazurin assay were used to determine the minimum inhibitory concentration and minimum biofilm eradication concentration for planktonic and biofilm forms, respectively. Results showed that Ag NPs and gentamicin combinations had synergistic antibacterial activity against P. aeruginosa planktonic and biofilm forms and MRSA biofilms. Furthermore, additive effects against biofilms were seen for combinations of Ag NPs with tobramycin or ciprofloxacin against P. aeruginosa; with mupirocin against MRSA; and with augmentin, doxycycline, azithromycin and clindamycin against S. aureus. Moreover, additive effects against planktonic forms were observed for combinations of Ag NPs with tobramycin, ciprofloxacin, imipenem, ceftazidime and aztreonam against P. aeruginosa; with gentamicin or linezolid against MRSA; and with doxycycline or clindamycin against S. aureus. In conclusion, Ag NP-antibiotic combinations can result in enhanced antimicrobial action against P. aeruginosa, MRSA and S. aureus clinical isolates in planktonic and biofilm forms and can be used in the context of CRS with confirmed infection.
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http://dx.doi.org/10.1016/j.pathol.2021.08.014DOI Listing
June 2022

Green synthesized colloidal silver is devoid of toxic effects on primary human nasal epithelial cells in vitro.

Food Chem Toxicol 2021 Nov 12;157:112606. Epub 2021 Oct 12.

Department of Surgery-Otolaryngology Head and Neck Surgery, Basil Hetzel Institute for Translational Health Research, Central Adelaide Local Health Network, Woodville, South, Australia; The University of Adelaide, Adelaide, Australia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.fct.2021.112606DOI Listing
November 2021

Trimellitic anhydride facilitates transepithelial permeability disrupting tight junctions in sinonasal epithelial cells.

Toxicol Lett 2021 Dec 7;353:27-33. Epub 2021 Oct 7.

Department of Surgery-Otolaryngology, Head and Neck Surgery, University of Adelaide, Adelaide, South Australia, Australia; Basil Hetzel Institute for Translational Health Research, Central Adelaide Local Health Network, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.toxlet.2021.09.016DOI Listing
December 2021

Preclinical Development of a Bacteriophage Cocktail for Treating Multidrug Resistant Infections.

Microorganisms 2021 Sep 21;9(9). Epub 2021 Sep 21.

Department of Health and Medical Sciences-Surgery, The University of Adelaide, Adelaide 5000, Australia.

A () airway infection is one of the predominant causes contributing to the high morbidity and mortality rates in cystic fibrosis (CF) patients. The emergence of antibiotic resistant strains has led to an urgent need for new therapeutic approaches. Bacteriophages (phages) are viruses that can infect and lyse specific bacteria, providing a potential alternative approach in targeting antibiotic-resistant strains. We aim to isolate and characterise novel phages for combination in a cocktail to kill One particular phage, PA4, could lyse 14/20 clinical isolates as observed through spot assays. This phage could significantly reduce the growth of bacteria in vitro, as determined through planktonic adsorption and inhibition assays as well as crystal violet- and LIVE/DEAD-stained biofilm assays. A morphological and genomic analysis revealed that PA4 belongs to the Myoviridae family and contained 66,450 bp. The broad infectivity profile, good stability in various pH and temperature conditions, lytic ability and the absence of the absences of antibiotic resistance, toxic and lysogenic genes suggest that PA4 is a good candidate for clinical grade use. Overall, phage therapy represents a promising alternative treatment option to antibiotics when treating a infection.
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http://dx.doi.org/10.3390/microorganisms9092001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464757PMC
September 2021

The effect of chemical and structural modifiers on the haemostatic process and cytotoxicity of the beta-chitin patch.

Sci Rep 2021 09 17;11(1):18577. Epub 2021 Sep 17.

Department of Surgery-Otorhinolaryngology, Head and Neck Surgery, University of Adelaide, Adelaide, Australia.

Beta-chitin patch has previously been proven to be an effective haemostat, but whether modifying the patch affects its efficacy and safety, remains unanswered. In this study, the patch was modified using polyethylene oxide, Pluronic-F127, calcium, increased thickness or polyphosphate, and their effect on the process of haemostasis and cytotoxicity was tested and compared with standard-of-care, Surgicel and FloSeal. Whole blood collected from volunteers was applied to the patches to test their whole blood clotting and thrombin generation capacities, whilst platelet isolates were used to test their platelet aggregation ability. The fluid absorption capacity of the patches was tested using simulated body fluid. Cytotoxicity of the patches was tested using AlamarBlue assays and PC12 cells and the results were compared with the standard-of-care. In this study, beta-chitin patch modifications failed to improve its whole blood clotting, platelet aggregation and thrombin generation capacity. Compared to non-modified patch, modifications with polyethylene oxide or calcium reduced platelet aggregation and thrombin generation capacity, while increasing the thickness or adding polyphosphate decreased platelet aggregation capacity. The cytotoxicity assays demonstrated that the beta-chitin patches were non-toxic to cells. In vivo research is required to evaluate the safety and efficacy of the beta-chitin patches in a clinical setting.
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http://dx.doi.org/10.1038/s41598-021-97781-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448852PMC
September 2021

Cytokine-Induced Modulation of SARS-CoV2 Receptor Expression in Primary Human Nasal Epithelial Cells.

Pathogens 2021 Jul 5;10(7). Epub 2021 Jul 5.

Department of Surgery-Otolaryngology, Head and Neck Surgery, Central Adelaide Local Health Network (Basil Hetzel Institute), The Queen Elizabeth Hospital and The University of Adelaide, Adelaide, AS 5011, Australia.

: Viral entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) via the spike protein enables endocytosis into host cells using the ACE2 receptor and TMPRSS2. The frequent upper respiratory tract symptoms of COVID-19 and the localization of the virus to the nasopharynx, the most common site of swabbing, indicate that the sinonasal mucosa may play an important role in SARS-CoV2 infection and viral replication. This paper investigates the presence of ACE2 receptor and TMPRESS2 expression in the primary human nasal epithelial cells (HNECs) from the following: chronic rhinosinusitis without nasal polyps (CRSsNP), CRS with nasal polyps (CRSwNP) and control (non-CRS) patients, and maps the expression changes when exposed to Th1, Th2, Th17-associated cytokines. We found that ACE2 and TMPRSS2 expression was higher in control HNECs than CRSwNP HNECs, and that both ACE2 and TMPRSS2 were downregulated further by Th2 cytokines in CRSwNP HNECs. This indicates an immune dysregulated state of CRSwNP mucosa, which normally contributes to a chronic inflammatory state, and might support an altered susceptibility to SARS-CoV2 infection and transmission.
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http://dx.doi.org/10.3390/pathogens10070848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308731PMC
July 2021

Acoustic drug delivery to the maxillary sinus.

Int J Pharm 2021 Sep 23;606:120927. Epub 2021 Jul 23.

Department of Surgery - Otolaryngology Head and Neck Surgery, The University of Adelaide, Adelaide, SA, Australia.

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.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120927DOI Listing
September 2021

Optimal primer selection for sinus microbiome profiling: A comparative analysis of the V1-V3 and V3-4 16S target regions.

Int Forum Allergy Rhinol 2021 12 9;11(12):1698-1702. Epub 2021 Jul 9.

Department of Otolaryngology Head and Neck Surgery, University of Adelaide, Woodville South, South Australia, Australia.

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http://dx.doi.org/10.1002/alr.22858DOI Listing
December 2021

Association between mucosal barrier disruption by Pseudomonas aeruginosa exoproteins and asthma in patients with chronic rhinosinusitis.

Allergy 2021 11 9;76(11):3459-3469. Epub 2021 Jun 9.

Department of Surgery-Otolaryngology, Head and Neck Surgery, University of Adelaide, Adelaide, South Australia, Australia.

Background: Chronic rhinosinusitis (CRS) is a common chronic respiratory condition, frequently associated with asthma and affecting the majority of cystic fibrosis (CF) patients. Pseudomonas aeruginosa infections and biofilms have been implicated in recalcitrant CRS. One of the mechanisms of action for bacteria in CRS and CF is mucosal barrier disruption by secreted products that contribute to the inflammation. However, the role of biofilm and planktonic forms of P. aeruginosa in this process is not known. The aim is to determine the effect of P. aeruginosa exoproteins isolated from CF and non-CF CRS patients on the mucosal barrier.

Methods: Exoproteins from 40 P. aeruginosa isolates were collected in planktonic and biofilm forms and applied to air-liquid interface (ALI) cultures of primary human nasal epithelial cells (HNECs). Mucosal barrier integrity was evaluated by transepithelial electrical resistance (TEER), passage of FITC-dextrans and immunofluorescence of tight junction proteins. Cytotoxicity assays were performed to measure cell viability, and IL-6 ELISA was carried out to evaluate pro-inflammatory effects.

Results: Planktonic exoproteins from 20/40 (50%) clinical isolates had a significant detrimental effect on the barrier and significantly increased IL-6 production. Barrier disruption was characterized by a reduced TEER, increased permeability of FITC-dextrans and discontinuous immunolocalization of tight junction proteins and was significantly more prevalent in isolates harvested from patients with comorbid asthma (P < .05).

Conclusion: Exoproteins from planktonic P. aeruginosa clinical isolates from asthmatic CRS patients have detrimental effects on the mucosal barrier and induce IL-6 production potentially contributing to the mucosal inflammation in CRS patients.
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http://dx.doi.org/10.1111/all.14959DOI Listing
November 2021

Overcoming bacteriophage insensitivity in Staphylococcus aureus using clindamycin and azithromycinat subinhibitory concentrations.

Allergy 2021 11 16;76(11):3446-3458. Epub 2021 May 16.

Department of Surgery-Otolaryngology Head and Neck Surgery, Basil Hetzel Institute for Translational Health Research, Central Adelaide Local Health Network, Woodville South, SA, Australia.

Background: Staphylococcus aureus is a pathogen of major concern in both acute infections and chronic conditions such as chronic rhinosinusitis (CRS). Bacteriophage (phage) therapy has recently regained interest for its potential to treat infections caused by antibiotic resistant strains including Methicillin Resistant Staphylococcus aureus (MRSA). However, bacteria can adapt and become resistant to phages. The aim of this study is to determine the potential for antibiotics to overcome phage resistance.

Methods: The susceptibility of S. aureus clinical isolates (CIs) to phages J-Sa36, Sa83 and Sa87 alone or in combination with protein synthesis inhibitor (PSI) antibiotics clindamycin, azithromycin and erythromycin was assessed using plaque spot assays, minimum inhibitory concentration (MIC) assays, double layer spot assays and resazurin assays. The safety and efficacy of subinhibitory PSI antibiotics in combination with phage was tested in a Sprague Dawley rat model of sinusitis infected with a phage resistant S. aureus CI.

Results: All three antibiotics at subinhibitory concentrations showed synergy when combined with all 3 phages against S. aureus CIs in planktonic and biofilm form and could sensitize phage-resistant S. aureus to promote phage infection. The combination of topical subinhibitory clindamycin or azithromycin and phage was safe and could eradicate S. aureus sinonasal biofilms in vivo.

Conclusion: Subinhibitory concentrations of PSI antibiotics could sensitize phage-resistant S. aureus and MRSA strains to phages in vitro and in vivo. This data supports the potential use of phage-PSI antibiotic combination therapies, in particular for difficult-to-treat infections with phage-resistant S. aureus and MRSA strains.
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http://dx.doi.org/10.1111/all.14883DOI Listing
November 2021

Colloidal silver combating pathogenic Pseudomonas aeruginosa and MRSA in chronic rhinosinusitis.

Colloids Surf B Biointerfaces 2021 Jun 4;202:111675. Epub 2021 Mar 4.

Department of Surgery-Otolaryngology Head and Neck Surgery, Basil Hetzel Institute for Translational Health Research, Central Adelaide Local Health Network, Woodville South, Australia; The University of Adelaide, Adelaide, Australia. Electronic address:

The emergence of antibiotic resistant bacteria requires for the development of new antimicrobial compounds one of which colloidal silver (CS) having strong bactericidal properties and being the most promising inorganic nanoparticles for the treatment of bacterial infectious diseases. However, their production can be slow and cumbersome. Here, we used Corymbia maculata aqueous leaf extract as a reducing agent to synthesize CS in a single 15-minute process. CS was physico-chemically characterized for shape, size, zeta potential and stability. The Minimal Inhibitory Concentration (MIC) and Minimum Biofilm Eradication Concentration (MBEC) of CS against planktonic and biofilm forms of methicillin-resistant Staphylococcus aureus (MRSA, n = 5), Pseudomonas aeruginosa (n = 5), Haemophilus influenzae (n = 5) and Streptococcus pneumoniae (n = 3) chronic rhinosinusitis clinical isolates were investigated using the microdilution method and resazurin assay, respectively. The in vitro cytotoxicity on bronchial epithelial cells (Nuli-1) was analyzed by the crystal violet proliferation assay. The safety and efficacy of CS was evaluated in an in vivo infection model in Caenorhabditis elegans. CS was spherical in shape with a diameter of between 11-16 nm (TEM analysis) in dried form and 40 nm (NanoSight) in colloidal form and was stable at room temperature and 4 °C for one year. Average MIC and MBEC values varied between 11 and 44 ppm for MRSA, H. influenzae and S. pneumoniae and between 0.2 and 3 ppm for P. aeruginosa. CS was not toxic to Nuli-1 cells or C. elegans at concentrations of 44 ppm and reduced the Colony Forming Units counts by 96.9 % and 99.6 % in C. elegans for MRSA and P. aeruginosa, respectively. In conclusion, a novel, green synthesis of stable CS is demonstrated with good safety and efficacy profiles, particularly against P. aeruginosa in planktonic and biofilm forms. These CS have potential applications against clinical infections, including in the context of CRS.
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http://dx.doi.org/10.1016/j.colsurfb.2021.111675DOI Listing
June 2021

Has Antimicrobial Activity against and Methicillin-Resistant Pathogens Isolated from the Sinonasal Niche of Chronic Rhinosinusitis Patients.

Pathogens 2021 Feb 14;10(2). Epub 2021 Feb 14.

Department of Surgery-Otolaryngology, Head and Neck Surgery, The University of Adelaide, Basil Hetzel Institute for Translational Health Research, Central Adelaide Local Health Network, Woodville 5011, Australia.

is the predominant species of the healthy human nasal microbiota, and its relative abundance is decreased in the context of chronic rhinosinusitis (CRS). This study aimed to evaluate the antimicrobial potential of isolated from a healthy human nasal cavity against planktonic and biofilm growth of () and methicillin-resistant (MRSA) clinical isolates (CIs) from CRS patients. Nasal swabs from twenty non-CRS control subjects were screened for the presence of using microbiological and molecular techniques. CIs and their culture supernatants were tested for their antimicrobial activity against eight and eight MRSA 4CIs and ATCC25923. The anti-biofilm potential of cell-free culture supernatants (CFCSs) on biofilms was also assessed. Of the 20 nasal swabs, 10 CIs were identified and confirmed with gene sequencing. All isolates showed variable antimicrobial activity against eight out of 8 and seven out of eight MRSA CIs. Culture supernatants from all CIs exhibited a significant dose-dependent antibacterial activity ( < 0.05) against five out of five representative and MRSA CIs. This inhibition was abolished after proteinase K treatment. supernatants induced a significant reduction in metabolic activity and biofilm biomass of and MRSA CIs compared to untreated growth control ( < 0.05). exhibited antimicrobial activity against and MRSA CIs in both planktonic and biofilm forms and holds promise for the development of innovative probiotic therapies to promote sinus health.
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http://dx.doi.org/10.3390/pathogens10020207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918835PMC
February 2021

Metallothionein-3 is a clinical biomarker for tissue zinc levels in nasal mucosa.

Auris Nasus Larynx 2021 Oct 30;48(5):890-897. Epub 2021 Jan 30.

Department of Surgery-Otorhinolaryngology Head and Neck Surgery, the Queen Elizabeth Hospital, and the University of Adelaide, Adelaide, SA 5061, Australia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.anl.2021.01.019DOI Listing
October 2021

International consensus statement on allergy and rhinology: rhinosinusitis 2021.

Int Forum Allergy Rhinol 2021 03;11(3):213-739

Rutgers New Jersey Medical School, Newark, NJ.

I.

Executive Summary: BACKGROUND: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR-RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR-RS-2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence-based findings of the document.

Methods: ICAR-RS presents over 180 topics in the forms of evidence-based reviews with recommendations (EBRRs), evidence-based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary.

Results: ICAR-RS-2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence-based management algorithm is provided.

Conclusion: This ICAR-RS-2021 executive summary provides a compilation of the evidence-based recommendations for medical and surgical treatment of the most common forms of RS.
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http://dx.doi.org/10.1002/alr.22741DOI Listing
March 2021

Tertiary Lymphoid Organs: A Primer for Otolaryngologists.

Laryngoscope 2021 08 12;131(8):1697-1703. Epub 2020 Nov 12.

Department of Surgery - Otolaryngology, Head and Neck Surgery, The University of Adelaide, Adelaide, South Australia, Australia.

Objectives/hypothesis: Lymphoid neogenesis or the development of organised, de novo lymphoid structures has been described increasingly in chronically inflamed tissues. The presence of tertiary lymphoid organs (TLOs) has already been demonstrated to result in significant consequences for disease pathology, severity, prognosis and patient outcomes. Whilst the wider medical community has embraced TLOs as important markers of disease and potential therapeutic targets, the otolaryngology field has only begun turning to these entities in an academic capacity. This review aims to outline the role of tertiary lymphoid organs in disease and summarise key early findings in the ENT field. We also an overview of TLOs, their developmental process and clinicopathological implications.

Study Design: Literature review.

Methods: A literature search for all relevant peer-reviewed publications pertaining to TLOs and ENT diseases. Search was conducted using PubMed, Embase and CINAHL databases.

Results: A total of 24 studies were identified relevant to the topic. The majority of TLO research in ENT fell into the areas of oral squamous cell carcinoma (SCC) and chronic rhinosinusitis (CRS).

Conclusions: Early research into both oral SCC and CRS suggests that TLOs have significant roles within ear, nose and throat (ENT) diseases. At this point in time, however, TLOs remain somewhat a mystery amongst otolaryngologists. As information in this field increases, we may develop a better understanding of how lymphoid neogenesis can influence disease outcomes amongst our patients and, ultimately, how they can be utilised in an immunotherapeutic manner. Laryngoscope, 131:1697-1703, 2021.
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http://dx.doi.org/10.1002/lary.29261DOI Listing
August 2021
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