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The kinetics and equilibrium of the adsorption of Indanthrene Olive Green (IOG) from aqueous solution onto chitosan have been investigated. The chitosan was characterised in terms of its average degree of de-acetylation (DD) and by XRD, TGA/DTG, IR, SEM and specific BET surface area methods. Batch adsorptions experiments were carried out at different pH values and dye concentrations. It was found that the adsorption process was favoured by acidic pH conditions (4.0–6.0). The adsorption followed second-order rate kinetics and the experimental equilibrium data followed the Langmuir isotherm, thereby suggesting that chemisorption might be the major adsorption mode. Such adsorption also occurred on chitosan fibres, although to a significantly lower extent than on crushed chitosan. The corresponding thermodynamic parameters (ΔG 0 , ΔH 0 and ΔS 0 ) were calculated. The positive values obtained for ΔH 0 (161.7 kJ/mol) and ΔS 0 [559.9 J/(mol K)] suggest that the adsorption process was endothermic, with the randomness of the system increasing during the adsorption process. A simplified adsorption model has also been proposed.

Reduced sense of smell is a common symptom in patients with chronic rhinosinusitis (CRS). Although it is often under-diagnosed by healthcare providers, reduced sense of smell can have a substantial negative impact on patient's quality of life as measured by health-related quality of life (HRQoL) assessments and patient-reported outcomes. This narrative review describes current smell loss diagnosis and management guidelines in CRS, and the relationship between smell loss and CRS. Reduced sense of smell can be an indication of CRS disease severity in patients with (CRSwNP) and without nasal polyps (CRSsNP), and recovery of smell can be an indicator of successful CRS treatment. The current first-line therapeutic options for smell loss are intranasal corticosteroids and nasal irrigation, and second-line therapeutic options include systemic steroids and surgery. Shared decision-making between patient, caregiver, and healthcare provider is important when choosing the most appropriate CRS treatment option. Emerging biologic therapies that target type 2 inflammation signaling pathways, such as dupilumab, omalizumab, and mepolizumab, have been shown to improve smell and taste in randomized controlled trials of patients with CRSwNP.A graphical abstract and video abstract are available with this article., (© 2024. The Author(s).)

While primarily a sensory organ, the mammalian olfactory epithelium (OE) also plays a critical role as an immune barrier. Mechanisms governing interactions between the immune system and this specialized chemosensory tissue are gaining interest, in part sparked by the COVID-19 pandemic. Regulated inflammation is intrinsic to normal mucosal healing and homeostasis, but prolonged OE inflammation is associated with persistent loss of smell, belying the intertwining of local mucosal immunology and olfactory function. Evidence supports bidirectional communication between OE cells and the immune system in health and disease. Recent investigations suggest that neuro-immune cross-talk modulates olfactory stem cell behavior and neuronal regeneration dynamics, prioritizing the epithelial-like non-neuronal framework with immune barrier function at the expense of the neurosensory organ in chronic inflammation., Competing Interests: Declaration of interests The authors have declared that no conflict of interest exists., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Key Points: A persistent type 2 endotype signature exists in recalcitrant chronic rhinosinusitis with nasal polyps mucosa on dupilumab. Revision sinus surgery immediately prior to dupilumab reduces long-term interleukin (IL)-4/IL-13 tissue mRNA. Pre-dupilumab revision surgery is associated with reduced tissue eosinophils and GATA-3+ cells., (© 2024 ARS‐AAOA, LLC.)

Objective: To evaluate the association between smell loss and other aspects of disease, and evaluate dupilumab efficacy in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) and moderate or severe smell loss., Methods: This post-hoc analysis of the SINUS-24/52 studies (NCT02912468/NCT02898454) analyzed nasal polyp score (NPS, 0-8), nasal congestion/obstruction (NC, 0-3), Lund-Mackay CT-scan score (LMK-CT, 0-24), rhinosinusitis severity visual analog scale (RS-VAS, 0-10), and 22-item Sinonasal Outcome Test (SNOT-22, 0-110) according to baseline monthly average patient-reported loss of smell scores (LoS, 0-3) of >1 to 2 (moderate) or >2 to 3 (severe) in patients randomized to dupilumab 300 mg or placebo every 2 weeks., Results: Of 724 patients randomized, baseline LoS was severe in 601 (83%) and moderate in 106 (15%). At baseline, severe versus moderate LoS was associated with 1-point greater severity of NC (odds ratio [OR] 6.01 [95% confidence interval, (CI) 3.95, 9.15]), 5-point greater severity of LMK-CT (OR 2.19 [1.69, 2.85]), and 8.9-point greater severity of SNOT-22 (OR 1.35 [1.20, 1.49]). At Week 24, least squares mean differences (95% CI) dupilumab versus placebo in change from baseline were: NPS -1.90 (-2.56, -1.25) and -1.95 (-2.20, -1.70) in the moderate and severe baseline LoS subgroups, respectively; NC -.35 (-.64, -.06) and -1.00 (-1.13, -.87); LMK-CT -6.30 (-7.88, -4.72) and -6.22 (-6.82, -5.63); RS-VAS -1.18 (-2.20, -.16) and -3.47 (-3.90, -3.03); and SNOT-22 -7.52 (-14.55, -.48) and -21.72 (-24.63, -18.82); all nominal P  < .05 versus placebo. Improvements with dupilumab in NC, RS-VAS, and SNOT-22 were statistically greater in patients with severe versus moderate baseline LoS., Conclusion: Significant smell impairment in severe CRSwNP is associated with significant disease (NC, RS-VAS, LMK), health-related quality of life impairment (SNOT-22), asthma, and non-steroidal anti-inflammatory drug-exacerbated respiratory disease. Dupilumab significantly improved NPS, NC, LMK-CT, RS-VAS, and SNOT-22 in subjects with moderate and severe baseline smell loss., Competing Interests: Declaration of Conflicting InterestsThe authors declare the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Zachary M. Soler has been a consultant or advisory board member for Lyra, Novartis, Olympus, and Optinose; he has received speaker's fees from GlaxoSmithKline and Regeneron Pharmaceuticals Inc.; and held the post of medical director at Healthy Humming. Zara M. Patel has been a consultant or advisory board member for Dianosic, InfiniteMD, Mediflix, Medtronic, and Optinose and the Chief Medical Officer of Olfera Therapeutics. Joaquim Mullol has participated in a speakers’ bureau or advisory board or received a research grant from AstraZeneca, Genentech, Inc., GlaxoSmithKline, Glenmark, Menarini, Mitsubishi-Tanabe, Merck Sharp & Dohme, Viatris (Mylan-MEDA), Novartis, Procter & Gamble, Regeneron Pharmaceuticals Inc., Sanofi, and the NOUCOR/Uriach Group. Jose Mattos has no financial disclosures or conflicts of interest. Scott Nash, Changming Xia, Zhixiao Wang, Harry Sacks, and Yamo Deniz are employees of Regeneron Pharmaceuticals and may hold stock and/or stock options in the company. Kinga Borsos is a former employee of Sanofi and may hold stock and/or stock options in the company. Mark Corbett, Juby A. Jacob-Nara, and Paul Rowe are employees of Sanofi and may hold stock and/or stock options in the company. Andrew P. Lane is a member of the advisory boards of Sanofi and Regeneron Pharmaceuticals Inc.

Mechanisms of tumorigenesis in sinonasal squamous cell carcinoma (SNSCC) remain poorly described due to its rare nature. A subset of SNSCC are associated with the human papillomavirus (HPV); however, it is unknown whether HPV is a driver of HPV-associated SNSCC tumorigenesis or merely a neutral bystander. We hypothesized that performing the first large high-throughput sequencing study of SNSCC would reveal molecular mechanisms of tumorigenesis driving HPV-associated and HPV-independent SNSCC and identify targetable pathways. High-throughput sequencing was performed on 64 patients with HPV-associated and HPV-independent sinonasal carcinomas. Mutation annotation, viral integration, copy number, and pathway-based analyses were performed. Analysis of HPV-associated SNSCC revealed similar mutational patterns observed in HPV-associated cervical and head and neck squamous cell carcinoma, including lack of TP53 mutations and the presence of known hotspot mutations in PI3K and FGFR3. Further similarities included enrichment of APOBEC mutational signature, viral integration at known hotspot locations, and frequent mutations in epigenetic regulators. HPV-associated SNSCC-specific recurrent mutations were also identified including KMT2C , UBXN11 , AP3S1 , MT-ND4 , and MT-ND5 . Mutations in KMT2D and FGFR3 were associated with decreased overall survival. We developed the first known HPV-associated SNSCC cell line and combinatorial small molecule inhibition of YAP/TAZ and PI3K pathways synergistically inhibited tumor cell clonogenicity. In conclusion, HPV-associated SNSCC and HPV-independent SNSCC are driven by molecularly distinct mechanisms of tumorigenesis. Combinatorial blockade of YAP/TAZ and vertical inhibition of the PI3K pathway may be useful in targeting HPV-associated SNSCC whereas targeting MYC and horizontal inhibition of RAS/PI3K pathways for HPV-independent SNSCC., One Sentence Summary: This study solidifies HPV as a driver of HPV-associated SNSCC tumorigenesis, identifies molecular mechanisms distinguishing HPV-associated and HPV-independent SNSCC, and elucidates YAP/TAZ and PI3K blockade as key targets for HPV-associated SNSCC.

Smell deficits and neurobiological changes in the olfactory bulb (OB) and olfactory epithelium (OE) have been observed in schizophrenia and related disorders. The OE is the most peripheral olfactory system located outside the cranium, and is connected with the brain via direct neuronal projections to the OB. Nevertheless, it is unknown whether and how a disturbance of the OE affects the OB in schizophrenia and related disorders. Addressing this gap would be the first step in studying the impact of OE pathology in the disease pathophysiology in the brain. In this cross-species study, we observed that chronic, local OE inflammation with a set of upregulated genes in an inducible olfactory inflammation (IOI) mouse model led to a volume reduction, layer structure changes, and alterations of neuron functionality in the OB. Furthermore, IOI model also displayed behavioral deficits relevant to negative symptoms (avolition) in parallel to smell deficits. In first episode psychosis (FEP) patients, we observed a significant alteration in immune/inflammation-related molecular signatures in olfactory neuronal cells (ONCs) enriched from biopsied OE and a significant reduction in the OB volume, compared with those of healthy controls (HC). The increased expression of immune/inflammation-related molecules in ONCs was significantly correlated to the OB volume reduction in FEP patients, but no correlation was found in HCs. Moreover, the increased expression of human orthologues of the IOI genes in ONCs was significantly correlated with the OB volume reduction in FEP, but not in HCs. Together, our study implies a potential mechanism of the OE-OB pathology in patients with psychotic disorders (schizophrenia and related disorders). We hope that this mechanism may have a cross-disease implication, including COVID-19-elicited mental conditions that include smell deficits., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Olfactory dysfunction (OD) is increasingly recognized as a hallmark of unhealthy aging and is intimately associated with mortality, but therapies remain elusive. Recognizing the increased prevalence of OD in individuals with diabetes, and the potential anti-aging effects of metformin, we studied the association of metformin use with OD., Methods: Cross-temporal study of participants from Waves 2 (2010-11) and 3 (2015-16) of the National Social Life, Health, and Aging Project (NSHAP), a nationally representative cohort study of community-dwelling older adults. We included participants with diabetes who had complete data on olfaction and relevant covariates at Wave 2 and were not lost to follow-up at Wave 3. Olfactory identification (OI), the ability to identify the odorant, and olfactory sensitivity (OS), the ability to detect the presence of an odorant, were tested. Weighted multivariable logistic regression was used to study the association between metformin use at Wave 2 (baseline) and odds of having impaired OI/OS at Wave 3, adjusted for age, sex, race/ethnicity, education, smoking, BMI, HbA1c, years since diabetes diagnosis, and insulin use., Results: Among 228 participants with diabetes (mean age=70 years, 53% female, 21% Black), 112 (49%) used metformin at baseline. Relative to nonusers, users had 58% lower odds of impaired OI and 67% lower odds of impaired OS at Wave 3. Among participants with normal baseline OS (N=62), users had 97% lower odds of impaired OS at Wave 3., Conclusions: Metformin use is associated with lower odds of OD among individuals with diabetes, suggesting a potential protective effect on olfaction. Future work including a larger sample and additional information on metformin use is needed to establish whether these findings are independent of diabetic control.

SARS-CoV-2 infection of the upper airway and the subsequent immune response are early, critical factors in COVID-19 pathogenesis. By studying infection of human biopsies in vitro and in a hamster model in vivo, we demonstrated a transition in nasal tropism from olfactory to respiratory epithelium as the virus evolved. Analyzing each variant revealed that SARS-CoV-2 WA1 or Delta infect a proportion of olfactory neurons in addition to the primary target sustentacular cells. The Delta variant possessed broader cellular invasion capacity into the submucosa, while Omicron displayed enhanced nasal respiratory infection and longer retention in the sinonasal epithelium. The olfactory neuronal infection by WA1 and the subsequent olfactory bulb transport via axon were more pronounced in younger hosts. In addition, the observed viral clearance delay and phagocytic dysfunction in aged olfactory mucosa were accompanied by a decline of phagocytosis-related genes. Further, robust basal stem cell activation contributed to neuroepithelial regeneration and restored ACE2 expression postinfection. Together, our study characterized the nasal tropism of SARS-CoV-2 strains, immune clearance, and regeneration after infection. The shifting characteristics of viral infection at the airway portal provide insight into the variability of COVID-19 clinical features, particularly long COVID, and may suggest differing strategies for early local intervention.

Key Points: Metformin treatment is associated with reduced olfactory dysfunction (OD) in diabetic patients Metformin may possess potential protective effects on olfaction beyond glycemic control., (© 2023 ARS-AAOA, LLC.)

Objectives: The objective of this study was to characterize the associations of sensory impairments, including olfaction (OI), vision (VI), hearing (HI), and touch (TI), with telomere length (TL) in a group of community-dwelling older adults who participated in the Health ABC study., Methods: Across 1603 participants, OI was classified with the Brief Smell Identification Test (<11), HI with pure-tone averages (<25 dB), VI with visual acuity (20/50 or worse), and TI with monofilament testing (inability to detect three of four touches). Shorter TL was defined as the lowest quartile of sample TLs. Adjusted multivariable regressions were used to examine the cross-sectional association between the modality, severity, and number of sensory impairments with TL., Results: Participants had an average age of 77.4 ± 2.84 years, and 89.7% (n = 1438) had at least one or more sensory impairments. Severe OI (odds ratio [OR] = 1.73, 95% confidence interval [CI] = [1.19, 2.6]) was independently associated with increased odds of shorter TL. Additionally, having one (OR = 2.79, 95% CI = [1.69, 4.70]), two (OR = 2.5, 95% CI = [1.51, 4.26]), three (OR = 3.04, 95% CI = [1.79, 5.36]), or four impairments (OR = 3.72, 95% CI = [1.52, 7.33]) was associated with increased odds of shorter TL in a dose-dependent manner., Conclusion: Severe OI and TI appear to be particularly robust markers of shortened TL. Additionally, multiple sensory impairment is strongly associated with shortened TL, suggesting that sensory dysfunction may represent a unique biomarker of unhealthy aging., Level of Evidence: Level II Laryngoscope, 133:3132-3138, 2023., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Olfactory dysfunction is highly associated with chronic rhinosinusitis with nasal polyps (CRSwNP), and the severity of loss has been linked with biomarkers of type 2 inflammation. The ability of dupilumab to rapidly improve the sense of smell prior to improvement in polyp size suggests a direct role of IL-4/IL-13 receptor signaling in the olfactory epithelium (OE)., Methods: We created a transgenic mouse model in which IL-13 is inducibly expressed specifically within the OE. Gene expression analysis and immunohistology were utilized to characterize the effect of IL-13 on the structure of the OE., Results: After induction of olfactory IL-13 expression, there is a time-dependent loss of neurons from OE regions, accompanied by a modest inflammatory infiltrate. Horizontal basal cells undergo morphologic changes consistent with activation and demonstrate proliferation. Mucus production and increased expression of eotaxins is observed, with marked expression of Ym2 by sustentacular cells., Discussion: Chronic IL-13 exposure has several effects on the OE that are likely to affect function. The neuronal loss is in keeping with other models of allergic type 2 nasal inflammation. Future studies are needed to correlate cellular and molecular alterations in olfactory cell populations with findings in human CRSwNP, as well as to assess olfactory function in behavioral model systems., (© 2022 ARS-AAOA, LLC.)

Background: Chronic rhinosinusitis (CRS) is the leading cause of olfactory dysfunction in the general population. Olfactory dysfunction is more common in patients with CRS with nasal polyposis (CRSwNP) compared to those without polyps., Purpose: The present review aims to summarize the current literature on the mechanism behind olfactory dysfunction in CRSwNP and the impact of therapy on olfactory outcomes in this patient population., Methods: A comprehensive review of the available literature on olfaction in CRSwNP was performed. We evaluated the most recent evidence from studies on the mechanisms behind smell loss in CRSwNP and the impact of medical and surgical therapy for CRS on olfactory outcomes., Results: The mechanism behind olfactory dysfunction in CRSwNP is not completely understood, but evidence from clinical research and animal models suggests both an obstructive component causing conductive olfactory loss and an inflammatory response in the olfactory cleft leading to sensorineural olfactory loss. Oral steroids and endoscopic sinus surgery have both shown efficacy in improving olfactory outcomes in CRSwNP in the short term; however, the long-term response of these treatments remains uncertain. Newer targeted biologic therapies, such as dupilumab, have also shown remarkable and durable improvement in smell loss for CRSwNP patients., Conclusion: Olfactory dysfunction is highly prevalent in the CRSwNP population. Although significant advances have been made in our understanding of olfactory dysfunction in the setting of CRS, additional studies are needed to elucidate cellular and molecular changes mediated by type 2-mediated inflammation in the olfactory epithelium with potential downstream effects on the central olfactory system. Further identification of these underlying basic mechanisms will be vital for developing future therapies targeted to improve olfactory dysfunction in patients with CRSwNP.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) has been traditionally managed with a combination of topical and systemic medical therapy as well as endoscopic sinus surgery. The emergence of biologic therapies that target specific aspects of the inflammatory cascade has ushered in a potentially new paradigm in the management options available for CRSwNP., Purpose: To summarize the current literature and recommendations supporting the use of available biologic therapies for CRSwNP and to develop an algorithm to aid clinical decision-making regarding treatment selection., Methods: A review of available literature and studies that demonstrated the clinical efficacy of biologic agents for the treatment of CRSwNP informing current CRSwNP consensus algorithms., Results: Current biologic medications target immunoglobulin E, interleukins, or interleukin receptors implicated in the Th2 inflammatory cascade. Institution of biologic therapy is now an option for patients who have disease refractory to topical medical therapy and endoscopic sinus surgery, those who cannot tolerate surgery, or patients with other comorbid Th2 diseases. Response to treatment should be monitored at 4-6 months and 1 year after initiating therapy. Across multiple indirect comparisons, dupilumab appears to have the largest therapeutic benefit across multiple subjective and objective outcomes. The choice of therapeutic agent also depends on drug availability, patient tolerance, presence of comorbid illnesses, and cost., Conclusions: Biologics are emerging as an important option in the management of patients with CRSwNP. While more data is required to fully inform indications, treatment selection, and health economics related to their use, biologics may offer robust symptom relief to patients who have failed other interventions.

Olfactory impairments contribute to the psychopathology of mental illnesses such as schizophrenia and depression. Recent neuroscience research has shed light on the previously underappreciated olfactory neural circuits involved in regulation of higher brain functions. Although environmental factors such as air pollutants and respiratory viral infections are known to contribute to the risk for psychiatric disorders, the role of nasal inflammation in neurobehavioral outcomes and disease pathophysiology remains poorly understood. Here, we will first provide an overview of published findings on the impact of nasal inflammation in the olfactory system. We will then summarize clinical studies on olfactory impairments in schizophrenia and depression, followed by preclinical evidence on the neurobehavioral outcomes produced by olfactory dysfunction. Lastly, we will discuss the potential impact of nasal inflammation on brain development and function, as well as how we can address the role of nasal inflammation in the pathophysiological mechanisms underlying psychiatric disorders. Considering the current outbreak of Coronavirus Disease 2019 (COVID-19), which often causes nasal inflammation and serious adverse effects for olfactory function that might result in long-lasting neuropsychiatric sequelae, this line of research is particularly critical to understanding of the potential significance of nasal inflammation in the pathophysiology of psychiatric disorders., (© 2022. The Author(s).)

Background: Bitter and sweet taste receptors (T2Rs and T1Rs), respectively, are involved in the innate immune response of the sinonasal cavity and associated with chronic rhinosinusitis (CRS). Growing evidence suggests extraoral TRs as relevant biomarkers, but the current understanding is incomplete. This systematic review synthesizes current evidence of extraoral taste receptors in CRS., Methods: PubMed, Embase, Cochrane, Web of Science, and Scopus were reviewed in accordance with Preferred Reporting Items for Systemic Reviews and Meta-Analyses guidelines and included studies of genotypic and phenotypic T2R/T1R status in CRS patients., Results: Twenty-two studies with 3845 patients were included. Seventeen studies evaluated genotype and 10 evaluated taste phenotypes. Four of 6 studies examining the haplotype distribution of the T2R, TAS2R38, demonstrated increased AVI/AVI haplotype ("nontaster") frequency in CRS. Meanwhile, 2 studies demonstrated decreased bitter sensitivity in CRS with nasal polyposis (CRSwNP), whereas 3 other studies reported decreased bitter sensitivity only in CRS without nasal polyposis (CRSsNP). Findings regarding sweet sensitivity were mixed. Three studies with cystic fibrosis patients (n = 1393) were included. Studies investigating the association between clinical outcomes and TAS2R38 alleles were limited, but the nonfunctional combination of AVI/AVI was associated with increased utilization of sinus surgery and, in CRSsNP patients, with poorer improvement of symptoms postoperatively., Conclusion: Both genotypic and phenotypic assessments of T2Rs suggest a potential association with CRS, particularly CRSsNP. However, limited evidence and mixed conclusions cloud the role of T2Rs in CRS. Future investigations should aim to increase diverse populations, broaden institutional diversity, examine T1Rs, and utilize uniform assessments., (© 2021 ARS-AAOA, LLC.)

Background: Frailty is a syndrome characterized by reduced physiologic reserve and increased vulnerability to poor health outcomes. Disruption of sensorineural function appears to serve as a novel biomarker of frailty. Using population-level data, we sought to characterize the association between otolaryngic sensory dysfunction and frailty., Methods: A cross-sectional analysis of the 2011-2012 US National Health and Nutrition Examination Survey was performed on adults ≥40 years of age (n = 2138). Participants were grouped by subjective gustatory dysfunction (sGD), olfactory dysfunction (sOD), hearing loss (sHL), and measured hearing loss (mHL) with pure tone averages (PTAs). Frailty was operationalized using a continuous 36-item frailty index (FI) scored from 0 to 1, stratified in 4 categories ("non-frail," "vulnerable," "frail," or "most frail")., Results: All sensory loss groups had significantly higher FI scores than those without sensory loss (sGD = 0.15; sOD = 0.14; sHL = 0.15; low-frequency mHL = 0.16; high-frequency mHL = 0.14 vs control = 0.11; p < 0.007 for all). "Vulnerable" individuals had increased odds of sOD (adjusted odds ratio [aOR], 1.45; 95% confidence interval [CI], 1.05-2.00), whereas "frail" individuals had increased odds of sOD (aOR, 1.85; 95% CI, 1.26-2.71) and low-frequency mHL (aOR, 4.01; 95% CI, 1.27-12.63). The "most frail" individuals had increased odds of sHL (aOR, 11.72; 95% CI, 2.88-47.66) and high-frequency mHL (aOR 5.10; 95% CI, 1.72-15.12). PTAs were linearly associated with FI (low: β = 10.15; 95% CI, 1.78-18.51; high: β = 19.85; 95% CI, 5.19-34.53)., Conclusion: Otolaryngic sensory loss is associated with increased frailty. Independent association of frailty with measures of olfaction and hearing suggests that olfactory and hearing assessments may help identify at-risk individuals with modifiable risk factors., (© 2021 ARS-AAOA, LLC.)

Background: The literature regarding clinical olfaction, olfactory loss, and olfactory dysfunction has expanded rapidly over the past two decades, with an exponential rise in the past year. There is substantial variability in the quality of this literature and a need to consolidate and critically review the evidence. It is with that aim that we have gathered experts from around the world to produce this International Consensus on Allergy and Rhinology: Olfaction (ICAR:O)., Methods: Using previously described methodology, specific topics were developed relating to olfaction. Each topic was assigned a literature review, evidence-based review, or evidence-based review with recommendations format as dictated by available evidence and scope within the ICAR:O document. Following iterative reviews of each topic, the ICAR:O document was integrated and reviewed by all authors for final consensus., Results: The ICAR:O document reviews nearly 100 separate topics within the realm of olfaction, including diagnosis, epidemiology, disease burden, diagnosis, testing, etiology, treatment, and associated pathologies., Conclusion: This critical review of the existing clinical olfaction literature provides much needed insight and clarity into the evaluation, diagnosis, and treatment of patients with olfactory dysfunction, while also clearly delineating gaps in our knowledge and evidence base that we should investigate further., (© 2022 ARS-AAOA, LLC.)

Several vaccines have been introduced to combat the coronavirus infectious disease-2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current SARS-CoV-2 vaccines include mRNA-containing lipid nanoparticles or adenoviral vectors that encode the SARS-CoV-2 Spike (S) protein of SARS-CoV-2, inactivated virus, or protein subunits. Despite growing success in worldwide vaccination efforts, additional capabilities may be needed in the future to address issues such as stability and storage requirements, need for vaccine boosters, desirability of different routes of administration, and emergence of SARS-CoV-2 variants such as the Delta variant. Here, we present a novel, well-characterized SARS-CoV-2 vaccine candidate based on extracellular vesicles (EVs) of Salmonella typhimurium that are decorated with the mammalian cell culture-derived Spike receptor-binding domain (RBD). RBD-conjugated outer membrane vesicles (RBD-OMVs) were used to immunize the golden Syrian hamster (Mesocricetus auratus) model of COVID-19. Intranasal immunization resulted in high titres of blood anti-RBD IgG as well as detectable mucosal responses. Neutralizing antibody activity against wild-type and Delta variants was evident in all vaccinated subjects. Upon challenge with live virus, hamsters immunized with RBD-OMV, but not animals immunized with unconjugated OMVs or a vehicle control, avoided body mass loss, had lower virus titres in bronchoalveolar lavage fluid, and experienced less severe lung pathology. Our results emphasize the value and versatility of OMV-based vaccine approaches., (© 2022 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)

Background: In the olfactory epithelium, mitotically active globose basal cells (GBCs) continuously replenish olfactory sensory neurons (OSNs) lost throughout life. Although an essential role of the transcription factor Sox2 in expanding olfactory progenitors/stem cells has been shown, its precise role in olfactory GBCs remain incompletely understood., Methods: We characterized the Sox2 expression in olfactory GBCs in normal conditions and in a lesion-regeneration model using a Lgr5EGFP-IRES-creERT2 strain. During GBC-mediated regeneration, genetic deletion of sox2 and lineage tracing experiments were performed to examine the function of Sox2 in the progeny of Lgr5-EGFP + GBCs., Results: Over 95% of Lgr5-EGFP + GBCs express Sox2 in normal or regeneration conditions. Loss of Sox2 dramatically reduces the cell number in each lineage traced cluster. In the progeny of Lgr5-EGFP + GBCs, loss of Sox2 significantly decreased the portion of OMP + OSNs. However, the generation of sustentacular cells was unchanged., Conclusions: Our observations support an essential role of Sox2 in adult olfactory regeneration, likely acting on neuronal-lineage GBCs., (© 2021 ARS-AAOA, LLC.)

Background: Our ability to smell and taste is dictated by 3 chemosensory systems with distinct physiologic mechanisms - olfaction, gustation, and chemesthesis. Although often overlooked, dysfunction of these special senses may have broad implications on multiple facets of patients' lives -including safety, nutritional status, quality of life, mental health, and even cognitive function. As "loss of smell or taste" emerged as a common symptom of coronavirus disease 2019 (COVID-19), the importance of intact chemosensory function has been thrust into the spotlight. Despite the growing recognition of chemosensory dysfunction, this already highly prevalent condition will increasingly impact a larger and more diverse population, highlighting the need for improved awareness and care of these patients., Methods: Comtemporary review of chemosensory function and assessments., Conclusions: Although patient-reported chemosensory function measures highlight the ease of screening of chemosensory dysfunction, self-reported measures underestimate both the prevalence and degree of chemosensory dysfunction and do not adequately distinguish between olfaction, gustation, and chemesthesis. Meanwhile, psychophysical assessment tools provide opportunities for more accurate, thorough assessment of the chemosenses when appropriate. Primary care providers are uniquely situated to identify patients burdened by chemosensory dysfunction and raise patient and provider awareness about the importance of chemosensory dysfunction. Identification of chemosensory dysfunction, particularly olfactory dysfunction, may raise suspicion for many underlying medical conditions, including early detection of neurodegenerative conditions. Furthermore, identification and awareness of patients with chemosensory dysfunction may help primary care providers to identify those who may benefit from additional therapeutic and safety interventions, or consultations with specialists for more detailed evaluations and management., Competing Interests: Conflicting and competing interests: Consulting, Healthy Humming, Stryker, and Optinose (RJS); grant support, Healthy Humming, Stryker, Optinose, GSK, Roche (RJS); grant support, Optinose (NRR); Sanofi-Regeneron Advisory Board (APL). All other authors declare no conflicts or competing interests., (© Copyright 2022 by the American Board of Family Medicine.)

Background: ARF nucleotide-binding site opener (ARNO) is a guanine nucleotide-exchange factor for ADP-ribosylation factor proteins. ARF nucleotide-binding site opener also binds MyD88, and small-molecule inhibition of ARNO reduces inflammation in animal models of inflammatory arthritis and acute inflammation. However, whether genetic deletion of Arno in mice reduces pathologic inflammation has not yet been reported. Furthermore, its role in the nasal cavity has yet to be investigated., Objective: To generate Arno knockout mice and to determine whether genetic loss of ARNO reduces eosinophilic inflammation in the ovalbumin (OVA) murine model of rhinitis., Methods: Arno knockout mice were generated and wild type and knockout littermates were subjected to the OVA-induced mouse model of rhinosinutitis. Eosinophilic inflammation was assessed through immunofluorescent quantification of EMBP + eosinophils in the septal mucosa and cytokine expression was assessed by quantitative polymerase chain reaction., Results: Arno knockout mice are viable and fertile without any noted deficits. Arno wild type and knockout mice subjected to the OVA-induced model of rhinitis demonstrated an average of 314.5 and 153.8 EMBP + cells per mm 2 septal tissue, respectively ( P < .05). Goblet cells per mm of basal lamina were assessed via Alcian blue and there was no statistically significant difference between Arno wild type and knockout mice. Ovalbumin-induced expression of interleukin-5 (IL-5) was significantly reduced in Arno knockout mice ( P < .05). There was no statistically significant reduction in IL-4, IL-13, or eotaxin-1 expression., Conclusions: These data demonstrate that deletion of Arno reduces eosinophilic inflammation and IL-5 expression in an OVA-induced model of rhinitis.

Allergic diseases arise in susceptible individuals in part because of decrements in protective pathways. The mechanism by which these anti-inflammatory molecules become repressed remains unclear. We have previously reported that epithelial dectin-1 prevents aberrant type 2 responses and is downregulated in the epithelium of allergic patients. Here, we report that dectin-1 is constitutively expressed by the respiratory epithelium in humans and that IL-33 specifically acts as a repressor of dectin-1. Mechanistically, this occurs via IL-33-dependent STAT3 activation and the subsequent repression of the dectin-1 gene, CLEC7A. We have identified a novel enhancer region upstream of the proximal promoter of CLEC7A that is only accessible in epithelial cells, but not in hematopoietic cells. Epigenetic repression of CLEC7A through this newly identified locus, downstream of an aberrant IL-33-STAT3 axis, occurs in the epithelium of allergic individuals. Collectively, our data identify a mechanism of epigenetic fine-tuning of dectin-1 expression in epithelial cells that may participate in allergenicity., (© 2021 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Epidemiological evidence suggests that adverse environmental factors in the nasal cavity may increase the risk for neuropsychiatric diseases. For instance, air pollution and nasal viral infection have been underscored as risk factors for Parkinson's disease, schizophrenia, and mood disorders. These adverse factors can elicit local inflammation in the nasal cavity, which may in turn influence higher brain function. Nevertheless, evidence that directly supports their causal link is missing. To fill this knowledge gap, we used an inducible mouse model for olfactory inflammation and showed the evidence that this local pathological factor can elicit behavioral abnormalities., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2021. Published by Elsevier B.V.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The 2014-15 influenza season saw the emergence of an H3N2 antigenic drift variant that formed the 3C.2a HA clade. Whole viral genomes were sequenced from nasopharyngeal swabs of ninety-four patients with confirmed influenza A virus infection and primary human nasal epithelial cell cultures used to efficiently isolate H3N2 viruses. The isolates were classified by HA clade and the presence of a new set of co-selected mutations in NA (a glycosylation site, NAg+) and PB1-F2 (H75P). The NA and PB1-F2 mutations were present in a subset of clade 3C.2a viruses (NAg+F2P), which dominated during the subsequent influenza seasons. In human nasal epithelial cell cultures, a virus with the novel NAg+F2P genotype replicated less well compared with a virus with the parental genotype. Retrospective analyses of clinical data showed that NAg+F2P genotype viruses were associated with increased cough and shortness of breath in infected patients., (© The Author(s) 2021. Published by Oxford University Press.)

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) can be a severe and debilitating disease associated with significant morbidity, loss of smell, sinus pressure and asthma exacerbations. Eosinophils play a role in the majority (85%) of patients. Benralizumab, an afucosylated monoclonal antibody directed against the IL-5 receptor, has powerful apoptotic effects on eosinophils., Objective: We sought to investigate the therapeutic benefit of inhibiting the IL-5 receptor using benralizumab to treat severe rhinosinusitis with nasal polyps., Methods: Patients with severe NP (defined by endoscopic grade 5 or more out of 8) with elevated eosinophils and a history of previous surgical or endoscopic polypectomy met entry criteria and were randomized in a double-blind fashion to receive 30 mg benralizumab SC or placebo. Endoscopic NP score was assessed at baseline and at treatment week 20. CT scan, SNOT-22 survey and UPSIT smell test score changes were also evaluated., Results: Thirty-three patients were screened, and twenty-four (n = 24) were enrolled in the study. Compared with baseline, benralizumab significantly improved NP score (-0.9 ± 0.2, P = 0.004) whereas placebo did not (-0.3 ± 0.3, P = 0.166). Benralizumab induced polyp size reduction compared with placebo did not reach statistical significance (P = 0.103). Five of 12 benralizumab-treated patients (42%) had improvements in all major outcomes (polyp score, CT, SNOT-22 and smell test) versus 2 out of 12 placebo (17%). The ratio of blood eosinophil count to allergen skin test positivity correlated with polyp reduction., Conclusion: Benralizumab was well-tolerated and compared with baseline achieved a statistically significant reduction in nasal polyp size, sinus occupancy, symptoms and improved sensation of smell for most patients (83%)., (© 2021 John Wiley & Sons Ltd.)

Importance: Anosmia, the loss of the sense of smell, has profound implications for patient safety, well-being, and quality of life, and it is a predictor of patient frailty and mortality. Exposure to air pollution may be an olfactory insult that contributes to the development of anosmia., Objective: To investigate the association between long-term exposure to particulate matter (PM) with an aerodynamic diameter of no more than 2.5 μm (PM2.5) with anosmia., Design, Setting, and Participants: This case-control study examined individuals who presented from January 1, 2013, through December 31, 2016, at an academic medical center in Baltimore, Maryland. Case participants were diagnosed with anosmia by board-certified otolaryngologists. Control participants were selected using the nearest neighbor matching strategy for age, sex, race/ethnicity, and date of diagnosis. Data analysis was conducted from September 2020 to March 2021., Exposures: Ambient PM2.5 levels., Main Outcomes and Measures: Novel method to quantify ambient PM2.5 exposure levels in patients diagnosed with anosmia compared with matched control participants., Results: A total of 2690 patients were identified with a mean (SD) age of 55.3 (16.6) years. The case group included 538 patients with anosmia (20%), and the control group included 2152 matched control participants (80%). Most of the individuals in the case and control groups were women, White patients, had overweight (BMI 25 to <30), and did not smoke (women: 339 [63.0%] and 1355 [63.0%]; White patients: 318 [59.1%] and 1343 [62.4%]; had overweight: 179 [33.3%] and 653 [30.3%]; and did not smoke: 328 [61.0%] and 1248 [58.0%]). Mean (SD) exposure to PM2.5 was significantly higher in patients with anosmia compared with healthy control participants at 12-, 24-, 36-, 60-month time points: 10.2 (1.6) μg/m3 vs 9.9 (1.9) μg/m3; 10.5 (1.7) μg/m3 vs 10.2 (1.9) μg/m3; 10.8 (1.8) μg/m3 vs 10.4 (2.0) μg/m3; and 11.0 (1.8) μg/m3 vs 10.7 (2.1) μg/m3, respectively. There was an association between elevated PM2.5 exposure level and odds of anosmia in multivariate analyses that adjusted for age, sex, race/ethnicity, body mass index, alcohol or tobacco use, and medical comorbidities (12 mo: odds ratio [OR], 1.73; 95% CI, 1.28-2.33; 24 mo: OR, 1.72; 95% CI, 1.30-2.29; 36 mo: OR, 1.69; 95% CI, 1.30-2.19; and 60 mo: OR, 1.59; 95% CI, 1.22-2.08). The association between long-term exposure to PM2.5 and the odds of developing anosmia was nonlinear, as indicated by spline analysis. For example, for 12 months of exposure to PM2.5, the odds of developing anosmia at 6.0 µg/m3 was OR 0.79 (95% CI, 0.64-0.97); at 10.0 µg/m3, OR 1.42 (95% CI, 1.10-1.82); at 15.0 µg/m3, OR 2.03 (95% CI, 1.15-3.58)., Conclusions and Relevance: In this study, long-term airborne exposure to PM2.5 was associated with anosmia. Ambient PM2.5 represents a potentially ubiquitous and modifiable risk factor for the loss of sense of smell.

Objectives/hypothesis: Oxidative stress has been postulated to play an important role in chronic rhinosinusitis. Nrf2 is a transcription factor that is involved in the regulation of multiple antioxidant genes, and its function has been previously shown to be important in sinonasal inflammation. Although the sinonasal implications of whole body Nrf2 -/- has been reported, the function of sinonasal epithelial expression of Nrf2 has not been studied. The primary aim of this study was to generate a mouse model that is genetically deficient in epithelial-specific Nrf2 and to understand its role in regulating sinonasal inflammation., Study Design: Basic science., Methods: An epithelial-specific Nrf2 knockout mouse was generated by crossing Krt5-cre(K5) with Nrf2 flox/flox . A papain-induced model of rhinosinusitis was performed in the resulting K5 Nrf2 -/- mouse. Immunohistochemistry was performed to quantify goblet cell hyperplasia. Mucosal cellular infiltrates were quantified using flow cytometry, and tissue cytokines were measured using an enzyme-linked immunosorbent assay. Lastly, the cellular source of type 2 cytokines was determined using intracellular cytokine staining., Results: Papain-sensitized mice lacking epithelial-specific Nrf2 demonstrate increased goblet cell hyperplasia, significant tissue eosinophilia, and statistically significant increase in mucosal IL-13 when compared to Nrf2 wild-type mice. Lastly, mucosal T cells were identified as the cellular source of IL-13., Conclusions: We demonstrate enhanced severity of eosinophilic sinonasal inflammation from disruption of the epithelial-specific Nrf2 pathway. The responsiveness of Nrf2-directed antioxidant pathways may act as a major determinant of susceptibility to eosinophilic inflammation and may have potential as a therapeutic target for chronic rhinosinusitis., Level of Evidence: NA Laryngoscope, 131:713-719, 2021., (© 2020 The American Laryngological, Rhinological and Otological Society, Inc.)

Current COVID-19 vaccine candidates are administered by injection and designed to produce an IgG response, preventing viremia and the COVID-19 syndrome. However, systemic respiratory vaccines generally provide limited protection against viral replication and shedding within the airway, as this requires a local mucosal secretory IgA response. Indeed, preclinical studies of adenovirus and mRNA candidate vaccines demonstrated persistent virus in nasal swabs despite preventing COVID-19. This suggests that systemically vaccinated patients, while asymptomatic, may still be become infected and transmit live virus from the upper airway. COVID-19 is known to spread through respiratory droplets and aerosols. Furthermore, significant evidence has shown that many clinic and surgical endonasal procedures are aerosol generating. Until further knowledge is acquired regarding mucosal immunity following systemic vaccination, otolaryngology providers should maintain precautions against viral transmission to protect the proportion of persistently vulnerable patients who exhibit subtotal vaccine efficacy or waning immunity or who defer vaccination.

Background: Interleukin 13 (IL-13) is a pleiotropic cytokine that has been shown to be important in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) and other type 2 inflammation-related diseases. Increased IL-13 expression can elicit several pro-inflammatory effects, including eosinophilia, and pathology such as increased mucus secretion. Polypogenesis in chronic rhinosinusitis (CRS) can be caused by hypoxia, which can also lead to hyperpermeability of airway epithelium and epithelium-to-mesenchymal translation through the upregulation of hypoxia-associated genes, such as HIF1. Whether T-helper 2 (Th2) inflammatory cytokines, such as IL-13, can also induce sinonasal epithelial hypoxia-associated genes is currently unknown., Methods: Human air-liquid interface (ALI) sinonasal epithelial cell cultures treated with recombinant IL-13 were analyzed by real-time polymerase chain reaction (PCR) and flow cytometry to determine the effect on epithelial cells., Results: Whole tissue from CRSwNP subjects showed increased HIF1A gene expression. Treatment of fully differentiated human ALI cultures with IL-13 resulted in a concurrent increase in HIF1A and ARNT messenger RNA (mRNA) expression. However, the level of EPAS1 expression was significantly reduced. IL-13 also had a dose-dependent response on the expression of HIF genes and the time course experiment showed peak expression of HIF1A and ARNT at 5 to 7 days poststimulation. Remarkably, CD73 surface expression also peaked at day 5 poststimulation., Conclusion: Our data suggests that IL-13 can induce hypoxia signaling pathway genes leading to surface expression of CD73, which has an anti-inflammatory effect., (© 2020 ARS-AAOA, LLC.)

Social health is a key aspect of active ageing. The objectives of this study are to investigate whether and what type of neighborhood third places are associated with positive social health among community dwelling older adults, and explore whether the associations vary by gender. Neighborhood third places are those spaces that have a social function and are located within a neighborhood, but outside the home (first place) and work (second place). Cross-sectional data were from 981 adults aged 55 years and older who responded to a survey conducted in 2018 in three Singapore neighborhoods. The neighborhoods were selected because they have a high percentage of older residents, different housing typologies, and heterogeneity of built environment qualities. Social health was measured using the six-item Lubben Social Network Scale. Attributes of participants' physical environment included residential density, pedestrian-friendly street design, access to public transport, and were objectively assessed using geographic information systems data. Covariates included age, sex, ethnic group, highest educational qualification, marital status, number of people living in dwelling, years living at current address, dwelling unit type, and number of diagnosed medical conditions and IADLs. Regression analysis was performed using Stata version 15 and indicated that female respondents who live in closer proximity to a wet market were more likely to have higher levels of social health independently of individual demographic and physical health characteristics, physical environment qualities, and other destination types. In a time of heightened concern about social isolation and loneliness among older age groups, this study contributes evidence that older people, particularly females, who live in closer proximity to a wet market self-reported better social health. Wet markets are spaces where people can mingle while purchasing or bargaining for fresh produce and household necessities. The mechanisms via which neighborhood third places may contribute to social health requires examination., Competing Interests: Declaration of competing interest The Authors declare that there is no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To examine how neighborhood-based cognitive and structural social capital are associated with individual quality of life among a sample of community-dwelling older adults in Singapore. Method: Using survey data from 981 older adults (aged 55 years and above) in nine residential neighborhoods, multilevel models simultaneously estimated the effects of independent variables at the individual and neighborhood levels on quality of life (CASP-12). Results: Social cohesion (β = 1.39, p < .01) and associational membership (β = 19.16, p < .01) were associated with higher quality of life in models adjusted for neighborhood facilities and individual sociodemographics, social networks, functional limitations, global cognitive status, and medical conditions. Discussion: The results suggest that place-based or neighborhood social capital may be important for older person's well-being. It identifies the contribution of structural (associational membership) and cognitive (social cohesion) social capital to the well-being of community-dwelling older adults in Singapore.

The molecular basis for the propensity of a small number of environmental proteins to provoke allergic responses is largely unknown. Herein, we report that mite group 13 allergens of the fatty acid-binding protein (FABP) family are sensed by an evolutionarily conserved acute-phase protein, serum amyloid A1 (SAA1), that promotes pulmonary type 2 immunity. Mechanistically, SAA1 interacted directly with allergenic mite FABPs (Der p 13 and Blo t 13). The interaction between mite FABPs and SAA1 activated the SAA1-binding receptor, formyl peptide receptor 2 (FPR2), which drove the epithelial release of the type-2-promoting cytokine interleukin (IL)-33 in a SAA1-dependent manner. Importantly, the SAA1-FPR2-IL-33 axis was upregulated in nasal epithelial cells from patients with chronic rhinosinusitis. These findings identify an unrecognized role for SAA1 as a soluble pattern recognition receptor for conserved FABPs found in common mite allergens that initiate type 2 immunity at mucosal surfaces.