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An anomalous winter phytoplankton bloom was observed across the central Gulf of Maine during a winter cruise in late February 1999, but not during a similar mission to the same region in late February 2000. During the cruise in 1999, 0 to 40 m mean chl a concentrations were >2 μg 1-1, while in 2000 total chl a concentrations were 5 pm size fractions were 10x more abundant in 1999 and included species typically not present in the central Gulf during winter. All developmental stages of planktonic copepods were present, including large numbers of older copepodid stages of species such as Calanus finmarchicus, indicating that the bloom had been proceeding for some time. RNA:DNA ratios of surface C. finmarchicus stage C5 and adult females were at or near maximum temperature-dependent values in 1999, but were considerably reduced in 2000. Egg production rates of C. finmarchicus were high in 1999 but reduced in 2000. Both showed a curvilinear relationship with chl a. Analysis of gonads of females of other copepod species indicate similar between-year differences in reproductive rates. We suggest that the presence of the winter bloom in the central Gulf of Maine allows an extra generation of C. finmarchicus and other copepods to develop, leading to a buildup of the population during winter. This will have significant effects on downstream regions such as Georges Bank, which depend on re-supply from the Gulf of Maine.

Objective: To assess the effect of allergen immunotherapy (AIT) on patients with central compartment atopic disease (CCAD) and house dust mite (HDM) sensitization post-surgery., Methods: A retrospective cohort of surgically treated, HDM-sensitized CRSwNP patients phenotyped as CCAD was assessed. Patients were divided into two groups based on whether they had AIT commenced as part of their surgical care. All AIT patients started immunotherapy prior to their surgery. The primary endpoint was reformation of middle turbinate (MT) edema 12 months postsurgery. Secondary endpoints were corticosteroid irrigation use (<4 times/week vs. ≥4 times/week, %) and the rhinologic domain of the 22-item sino-nasal outcome test (SNOT-22). Demographic characteristics, concomitant asthma, smoking status, history of aspirin-exacerbated respiratory disease, conjunctival symptoms, polysensitization, serum eosinophils (cell × 10 9 /L), tissue eosinophilia (% > 100/HPF), and serum IgE (kU/L) were also recorded., Results: Eighty-six CCAD patients were assessed (41 ± 14 yrs, 64% female). AIT was applied in 37% (n = 32). Baseline features were similar apart from greater conjunctival symptoms (72 vs. 45%, p = 0.02) in the AIT group. At 12 months post-surgery, the AIT group has less MT edema (% ≥ diffuse 15.6 vs. 52.9, p < 0.01). Patients on AIT also had less pharmacotherapy requirements at 12 months (% ≥ 4/week, 37.5 vs. 79.6%, p < 0.01). The rhinologic symptoms were similar (21.1 ± 17.1 vs. 20.1 ± 21.6, p = 0.83)., Conclusions: Surgery and pharmacotherapy are effective in managing CCAD, but the addition of AIT improved allergic phenomenon and allowed de-escalation of topical therapy. Longer term studies are required to demonstrate further immunomodulation., (© 2024 The Author(s). International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Background: Type 2 inflammation dominates eosinophilic chronic rhinosinusitis (eCRS) and adult onset asthma. IL-4, -5, and -13 are prominent disease mediators. Disease control can be achieved with biologic therapies. However, despite some patients entering remission, others experience poor control., Aim: We aimed to describe eCRS patients treated with anti-IL-5R antibody (benralizumab) and assess characteristics between responders and those requiring class switching to anti-IL-4/13R (dupilumab)., Method: A retrospective cohort study was performed on consecutive adult patients with eCRS and asthma who had commenced benralizumab.  Disease control was defined as controlled or poorly controlled (EPOS2020 partly control/uncontrolled). Poorly controlled patients were switched to dupilumab.  Baseline and post-IL-5R characteristics including age, sex, 22-item Sinonasal Outcome Test (SNOT-22), Asthma Control Questionnaire (ACQ) score, and serum/tissue eosinophilia were assessed. Disease control post-class switching was reassessed. Factors predicting poorly controlled disease on anti-IL-5R therapy were sought., Results: Fifty patients were assessed (51.44 ± 12.73 years, 56% female). Poorly controlled disease on anti-IL-5R requiring class switch to dupilumab was seen in 42%. Poorly controlled patients were younger (46.14 ± 10.76 vs. 55.28 ± 12.83 years, p = 0.01) with higher baseline SNOT-22 (61.42 ± 19.19 vs. 42.32 ± 21.55, p < 0.01). Baseline ACQ scores and eosinophil count (0.78 ± 0.49 vs. 0.62 ± 0.34 × 10 9 cells/L, p = 0.23) and were similar between groups. In the poorly controlled patients on anti-IL-5R therapy, eosinophilia had reduced in both serum (0.78 ± 0.5 vs. 0.02 ± 0.1 × 10 9 cells/L, p < 0.01) and tissue (>100 cells/HPF: 100% vs. 29%, p = 0.01). Class switching resulted in disease control for 65%., Conclusion: Neither eosinophilia nor its reduction predicted a non-responder group to anti-IL-5R therapy. While the eosinophil population may be a good marker for the CRS phenotype seen in nasal polyps, it is unlikely to be the cell population driving the disease process., (© 2025 The Author(s). International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Objective: Nasal airway surgery is often applied when treatment fails to relieve nasal obstruction. However, surgery that improves airflow does not always alleviate the symptoms of nasal obstruction. The perception of nasal breathing is likely more related to changes in mucosal temperature than the mechanical sensation of flow or pressure. This study aims to measure intranasal mucosal temperature pre-and post-surgery using endonasal thermal imaging, exploring its correlation with subjective nasal breathing and objective airflow measurements., Methods: A prospective study of adult patients with nasal obstruction managed with nasal airway surgery was performed. Intranasal mucosal temperatures were determined using the thermal endonasal image of the nasal passage produced by the infrared radiometric thermal camera (FILR VS290). A comparison was made between the mean values of mid-expiration (ExT) and mid-inspiration (InT) temperature data (internal nasal valve, nasal cavity, inferior turbinate, and overall airway [mean value]) and visual analog scale (VAS), Nasal Obstruction Symptom Evaluation (NOSE) scale and nasal airway resistance (NAR) before and after surgery., Results: Seven patients (35.14 ± 16.45 years, 57.14% female) were included. All NOSE, VAS, and NAR improved after surgery (59.29 ± 10.89 vs 17.14 ± 14.64; P  < .001, 64.50 ± 26.79 vs 18.57 ± 19.99; P  < .001, 0.82 ± 0.48 vs 0.34 ± 0.11 Pa/cm 3 /s; P  = .002, respectively). ExT, InT, and the difference between ExT and InT of three areas and overall airway were similar between pre-and post-surgery. No statistically significant correlations were found between intranasal mucosal temperature, VAS, NOSE, and NAR at pre-and post-surgery except for the difference between ExT and InT of overall airway and NOSE pre-operative (Pearson r  = 0.57; 95% CI 0.06-1.09; P  = .03)., Conclusion: Endonasal thermal imaging can assess the intranasal mucosal temperature of a patient. However, more precise imaging of the nasal passages and data acquisition are required to establish mucosal temperature as an objective measure of nasal obstruction before and after nasal airway surgery in a clinical setting., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RJ Harvey is consultant/advisory board with Medtronic, Novartis, Glaxo-Smith-Kline and Meda pharmaceuticals. He has received research grants from GSK, Sanofi, and Stallergenes. He has been on the speakers’ bureau for Glaxo-Smith-Kline, Astra-zeneca, Meda Pharmaceuticals and Seqirus. L Kalish is on the speakers’ bureau for Mylan, and Seqirus Pharmaceuticals. J Rimmer has honoraria with Sanofi Aventis, Novartis, Mundipharma, GSK, and Stallergenes. RG Campbell is on the speakers’ burea for Medtronic, Seqirus, GSK and Viatris. K Snidvongs received honoraria for speaking at symposia from Organon, Viatris, and Menarini. R Sacks is a consultant for Medtronic and is on the speakers bureau for Meda Pharmaceuticals. All other authors have no personal, financial, or institutional interest in any drugs, materials, or devices described in this article.

Rigidified nucleoside derivatives with (N)-methanocarba replacement of ribose have been repurposed as peripheral subtype-selective 5-HT 2B serotonin receptor antagonists for heart and lung fibrosis and intestinal/vascular conditions. 4'-Cyano derivative 40 (MRS8209; K i , 4.27 nM) was 47-fold (human binding, but not rat and mouse) and 724-fold (functionally) selective at 5-HT 2B R, compared to antitarget 5-HT 2C R, and predicted to form a stable receptor complex using docking and molecular dynamics. 4'-Cyano substituents enhanced 5-HT 2B R affinity (typically 4-5-fold compared to 4'-CH 2 OH), depending on an N 6 group larger than methyl. Asymmetric N 6 groups (4'-cyano-2-halo derivatives 33 - 35 and 37 ) provided potent 5-HT 2B R K i values (7-22 nM). A 4'-CH 2 CN substituent was less effective than 4'-CN at increasing 5-HT 2B R affinity, while a 4'-CHF 2 group produced high 5-HT 2B affinity/selectivity. A 2-benzylthio-adenine group with unsubstituted 6-NH 2 shifted the typical selectivity pattern toward potent 5-HT 2C binding. Thus, the SAR suggests that N 6 -cyclopentyl-4'-cyano modifications are promising, with an interdependence among the substituent positions.

Objectives: The aim was to assess the developmental attributes of sphenoid sinuses affected by fungal balls and describe a surgical approach which reestablishes gravity-dependent drainage to compensate for any mucociliary dysfunction., Methods: A within-patient case-control analysis was performed on sphenoid sinus dimensions from patients with sphenoid sinus fungal ball (SSFB). Radiological dimensions were assessed to determine the dominant or larger sinus by volume and width. Pneumatization in the sagittal and lateral extent was assessed. The influence of sinus size and pneumatization variants within a patient was analyzed. Patency and the presence of mucostasis from radical reshaping of the sinus cavity were documented at least 3 months after surgery. Complications (bleeding, cerebrospinal fluid leak, and cranial nerve palsy) were recorded., Results: Twenty-three patients (59 ± 19 years, 86% female, 46 sphenoid sinuses) were assessed. Fungal ball was more common in the smaller (non-dominant) sinus, by width (78% vs. 22%, p < 0.01) and by proportion of total sphenoid volume (0.39 ± 0.16 vs. 0.61 ± 0.16, p < 0.01). Pneumatization variants did not influence the development of SSFB within a patient. All patients had patency and the absence of mucostasis or persistent inflammation at last follow-up. No complications were reported., Conclusion: The smaller or nondominant sphenoid sinus is more affected by SSFB. Surgical reshaping of the sphenoid to prevent mucostasis is favorable in managing the smaller affected sinus cavity., Level of Evidence: 4 Laryngoscope, 134:4888-4892, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

The lateral recess of a well-pneumatized sphenoid sinus is challenging to access surgically. Traditional methods require the use of multiple angled endoscopes and curved instruments which may limit visualization. We describe a prelacrimal-transpterygoid/maxillary approach which offers direct access to this region with a 0° endoscope. Laryngoscope, 134:4918-4922, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: Endoscopic sinus and skull base surgery has led to significant improvements in patient outcomes, yet may have come at a cost to surgeons' musculoskeletal (MSK) health. We aimed to determine the prevalence and characteristics of work-related MSK disorders (WRMDs) in endoscopic sinus and skull base surgeons; to investigate contributing factors for WRMD in this population; and to evaluate the effectiveness of ergonomic interventions on the severity or prevalence of WRMD in this population., Data Sources: Medline, Embase, CINAHL, Web of Science, and Scopus from inception to April 2, 2024. A bibliographic examination was performed for further papers., Review Methods: Inclusion criteria included original peer-reviewed papers with work-related MSK outcomes (prevalence, contributing factors, and interventions) relating to endoscopic sinus and/or skull base surgeons in any language., Results: Of 25,772 unique citations, 37 studies met the inclusion criteria. The pooled lifetime, point, and 12-month prevalences of WRMD were 75.9% (95% confidence interval; I 2 , 67.2%-83.6%, I 2 95.6%), 80.8% (77.0%-84.3%, I 2 98.0%), and 82.0% (71.8%-90.3%, I 2 60.96%) respectively. The neck, lumbar spine, and thoracic spine were the most commonly involved areas. One of 9 studies on contributing factors investigated discomfort as an outcome. The remainder focussed on surrogate outcomes (eg, posture, hand dysfunction). Two of the 13 intervention studies investigated pain or fatigue as an outcome. The remainder targeted posture, muscle activity, or workload., Conclusion: WRMDs are highly prevalent in endoscopic sinus and skull base surgeons. Further studies focusing on the direct outcomes of WRMD such as pain are needed., (© 2024 The Author(s). Otolaryngology–Head and Neck Surgery published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Background: Radiomics is a quantitative approach to medical imaging, aimed to extract features into large datasets. By using artificial intelligence (AI) methodologies, large radiomic data can be analysed and translated into meaningful clinical applications. In rhinology, there is heavy reliance on computed tomography (CT) imaging of the paranasal sinus for diagnostics and assessment of treatment outcomes. Currently, there is an emergence of literature detailing radiomics use in rhinology., Objective: This systematic review aims to assess the current techniques used to analyze radiomic data from paranasal sinus CT imaging., Methods: A systematic search was performed using Ovid MEDLINE and EMBASE databases from January 1, 2019 until March 16, 2024 using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist and Cochrane Library Systematic Reviews for Diagnostic and Prognostic Studies. The QUADAS-2 and PROBAST tools were utilized to assess risk of bias., Results: Our search generated 1456 articles with 10 articles meeting eligibility criteria. Articles were divided into 2 categories, diagnostic (n = 7) and prognostic studies (n = 3). The number of radiomic features extracted ranged 4 to 1409, with analysis including non-AI-based statistical analyses (n = 3) or machine learning algorithms (n = 7). The diagnostic or prognostic utility of radiomics analyses were rated as excellent (n = 3), very good (n = 2), good (n = 2), or not reported (n = 3) based upon area under the curve receiver operating characteristic (AUC-ROC) or accuracy. The average radiomics quality score was 36.95%., Conclusion: Radiomics is an evolving field which can augment our understanding of rhinology diseases, however there are currently only minimal quality studies with limited clinical utility., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Richard J Harvey is a consultant/advisory board with Medtronic, Novartis, GSK and Meda pharmaceuticals. Research grant funding received from Glaxo-Smith-Kline. He has been on the speakers’ bureau for Glaxo-Smith-Kline, Astra-Zeneca, Meda Pharmaceuticals and Seqirus. Janet Rimmer has honoraria with Sanofi Aventis, Novartis, Mundipharma, BioCSL, Stallergenes. Larry Kalish is on the speakers’ bureau for Care Pharmaceuticals, Mylan and Seqirus Pharmaceuticals. Raymond Sacks is a consultant for Medtronic. Antonio Di Ieva has received research funding from B Braun, Abbott, Servier, and BrainLab. All other authors have no financial disclosures or conflicts of interest.

Background: With the recent proliferation of novel therapeutics for chronic rhinosinusitis with nasal polyps (CRSwNP), there is an immediate need for comprehensive means to assess CRSwNP disease status as well as to determine treatment efficacy. Outcome measures exist in different forms. Patient-reported outcome measures (PROMs) allow patients to provide direct input about their condition that is not possible to obtain in any other way. Common constructs that are measured using PROMs include quality of life or the burden of disease manifestations (e.g., symptom severity). Outcomes may also include the results of objective diagnostic testing/measurement of clinical signs or measured using psychophysical tests. Biomarkers represent an emerging class of outcome measures for CRSwNP and are chosen to directly reflect the active pathophysiologic processes of CRSwNP in the peripheral blood, sinus/polyp tissues, and sinonasal mucus., Methods: Narrative review of the literature, identifying and describing outcome measures that may be used in the evaluation of CRSwNP and for assessment of treatment responses., Results: In this review, we identify many different outcome measures for CRSwNP that fall under the categories of PROM, objective test, psychophysical test or biomarker. We describe the history of each - including seminal studies - and demonstrate the formal validation, psychometric performance, and limitations of each., Conclusions: PROMs, objective tests, psychophysical tests and biomarkers represent different classes of outcome measures that are complementary means of assessing CRSwNP disease status and treatment efficacy. The choice or interpretation of a CRSwNP outcome measure should be undertaken with full knowledge of its formal validation, psychometric performance, and limitations.

2-Arylethynyl (N)-methanocarba adenosine 5'-methylamides are selective A 3 adenosine receptor (AR) agonists containing a preestablished receptor-preferred pseudoribose conformation. Here, we compare analogues having bulky 2-substitution, either containing or lacking an ethynyl spacer between adenine and a cyclic group. 2-Aryl compounds 9 - 11 , 13 , 14 , 19 , 22 , 23 , 27 , 29 , 31 , and 34 , lacking a spacer, had human (h) A 3 AR K i values of 2-30 nM, and others displayed lower affinity. Mouse (m) A 3 AR affinity varied, with 2-arylethynyl having a higher affinity than 2-aryl analogues ( 7 , 8 > 3c , 3d > 3b ). However, 2-aryl-4'-truncated derivatives had greatly reduced hA 3 AR affinity, even containing affinity-enhancing N 6 -dopamine-derived substituents. Molecular modeling, including molecular dynamics simulation, predicted stable poses in the canonical A 3 AR agonist binding site, but 2-aryl (ECL2 interactions) and 2-arylethynyl (TM2 interactions) substituents have different conformations and environments. In a hA 3 AR miniGα i recruitment assay, 31 (MRS8062) was (slightly) more potent compared to a β-arrestin2 recruitment assay, both in engineered HEK293T cells, and its maximal efficacy ( E max ) was much higher (165%) than reference agonist NECA's. Thus, in the 2-aryl series, A 3 AR affinity and selectivity were variable and generally reduced compared to the 2-arylethynyl series, with a greater dependence on the specific aryl group present. Selected compounds were studied in vivo in an ischemic model of peripheral artery disease (PAD). Rigidified 2-arylethynyl analogues 3a - 3c were protective in this model of skeletal muscle ischemia-reperfusion injury/claudication, as previously shown only for moderately A 3 AR-selective ribosides or (N)-methanocarba derivatives. Thus, we have expanded the A 3 AR agonist SAR for (N)-methanocarba adenosines., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

Background: Nasal obstruction, triggered by allergic rhinitis, often does not resolve with allergen-specific immunotherapy (AIT) alone, thus inferior turbinate reduction surgery (ITR) may be required. This study aims to investigate the impact of combined treatment on nasal obstruction, as evidence is currently limited., Methodology/principal: A retrospective cohort study of perennial allergic rhinitis patients experiencing nasal obstruction and undergoing ≥12 months AIT was conducted. Two groups were derived, those undergoing AIT-with or without an ITR. Patient reported nasal obstruction (evaluated with questionnaires) and nasal airway function (Nasal Peak Inspiratory Flow [NPIF] and Nasal Airflow Resistance [NAR]) were monitored. The change from baseline to 12 months post-treatment in each group were compared., Results: A total of 118 patients (33.71 ± 14.43 years, 41.5% female) were recruited, 72% had AIT and 28% AIT&ITR. At baseline, the AIT&ITR group had a higher level of nasal obstruction (>moderate%; 63.6% vs 52.9%, P  = .048). Post treatment, AIT&ITR group reported greater reduction in nasal obstruction (>1 category change: 75.8% vs 48.2%, P  = .002). Similarly, the AIT&ITR group had greater improvement in nasal function by NPIF (-13.9 ± 110.3 L/minute vs -3.4 ± 78.1 L/minute, P  = .049) and NAR (-0.120 ± 0.342 Pa/cm³/second vs -0.093 ± 0.224 Pa/cm³/second, P  = .050)., Conclusions: Allergic rhinitis patients, with moderate to severe nasal obstruction, who undergo combined AIT&ITR have greater relief of nasal obstruction and improved airflow analysis compared to AIT alone., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Richard J Harvey is a consultant/advisory board with Medtronic, Novartis, GSK and Meda pharmaceuticals and received research grant funding from Glaxo-Smith-Kline. He has been on the speakers’ bureau for Glaxo-Smith-Kline, Astra-zeneca, Meda Pharmaceuticals, and Seqirus. Both Richard J Harvey and Raquel Alvarado have affiliations to the School of Clinical Medicine, St Vincent’s Healthcare Clinical Campus, Faculty of Medicine and Health, UNSW Sydney, Australia. Janet Rimmer has honoraria with Sanofi Aventis, Novartis, Mundipharma, BioCSL, Stallergenes. Raewyn Campbell has honoraria with Medtronic, Seqirus, Viatris, and Novartis steering committee. Larry Kalish is on the speakers’ bureau for Care Pharmaceuticals, Mylan, and Seqirus Pharmaceuticals.

Background: Biologic therapy targeting type 2 chronic rhinosinusitis with nasal polyps (CRSwNP) has greatly improved disease control but nonresponders exist in a proportion of patients in phase 3 trials and clinical practice. This study explores the serum and histologic changes in biologic treated CRSwNP that predict disease control., Methods: A cross-sectional study was performed of patients with CRSwNP on biologics for their asthma, who underwent endoscopic sinus surgery while on biologic therapy. At the 6-month postoperative assessment, patients with poorly controlled CRSwNP while on biologic therapy were compared to patients who were controlled. Blood and mucosal samples taken at the time of surgery 6 months prior were assessed to predict disease control., Results: A total of 37 patients were included (age 47.8 ± 12.4 years, 43.2% female). Those with poorly controlled disease had reduced tissue eosinophils (% >100 cells/high-powered field: 8.3% vs. 50.0%, p < 0.001) and increased serum neutrophils (5.2 ± 2.7 vs. 3.7 ± 1.1 × 10 9 cells/L, p = 0.02). Logistic regression analysis demonstrated that reduced tissue eosinophil was predictive for poorly controlled disease (OR = 0.21, 95% CI [0.05, 0.83], p = 0.03). Receiver-operating characteristic analysis showed that need for rescue systemic corticosteroid was predicted at a serum neutrophil cut-off level of 5.75 × 10 9 cells/L (sensitivity = 80.0%, specificity = 96.9%, AUC = 0.938, p = 0.002)., Conclusion: Low tissue eosinophils and increased serum neutrophils while on biologics predict for poor response in the biological treatment of with CRSwNP. A serum neutrophil level of ≥5.75 × 10 9 cells/L predicts for poor response to current biologic therapy., (© 2023 The Authors. International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Surgeons have a high rate of work-related musculoskeletal injuries; an area that has received little attention. These injuries result in surgeons performing less efficiently, needing to take time off work, suffering higher rates of burnout, and may ultimately lead surgeons to retire earlier than planned. Otorhinolaryngologists are at particular risk for work-related musculoskeletal injuries. Beyond the clinician, sustaining such injuries can negatively impact patient safety. Ergonomic interventions have been used effectively to reduce work-related musculoskeletal injuries in other professions, yet not in surgery. With traditional teachings of ideal body postures to avoid injury and manual handling training being re-evaluated, it is important to explore evidence based interventions for reducing work-related musculoskeletal injuries in otorhinolaryngologists. New research encourages us to shift the focus away from the traditional one-size-fits-all approach to ergonomics and toward postural recommendations and education that promote a dynamic, individualized approach to avoiding sustained, static and awkward postures., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose of Review: The upper and lower airways are inter-related despite serving different functions and can no longer be considered separately. Rhinologists are becoming increasingly aware of the role the lower airway plays in optimizing outcomes for their patients. This review highlights recent developments in pulmonology that impact rhinologic conditions., Recent Findings: The unified airway concept now supports the multidisciplinary management of respiratory and rhinologic pathologies. Biomarkers, biologics and the concept of treatable traits have permitted the development of personalized and precise treatment of the entire respiratory tract. The concept of corticosteroid stewardship, the introduction of steroid sparing agents for the treatment of respiratory diseases and the development of biomarkers, now forces us to be more considerate and precise with oral corticosteroid (OCS) prescribing and to consider reduction regimens. Finally, current research on climate change and vaping will allow us to better educate and prepare our patients to improve adherence and avoid exacerbations to maintain optimal global respiratory health., Summary: The inter-relatedness of the upper and lower airway has encouraged a multidisciplinary focus in respiratory medicine. More research is required to improve the precision respiratory medicine model, particularly in the realm of biomarkers and endotyping. These developments must also consider the impact of climate change, pollution and toxins for us to provide optimum care for our patients., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Microalgae are the main source of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), essential for the healthy development of most marine and terrestrial fauna including humans. Inverse correlations of algal EPA and DHA proportions (% of total fatty acids) with temperature have led to suggestions of a warming-induced decline in the global production of these biomolecules and an enhanced importance of high latitude organisms for their provision. The cold Arctic Ocean is a potential hotspot of EPA and DHA production, but consequences of global warming are unknown. Here, we combine a full-seasonal EPA and DHA dataset from the Central Arctic Ocean (CAO), with results from 13 previous field studies and 32 cultured algal strains to examine five potential climate change effects; ice algae loss, community shifts, increase in light, nutrients, and temperature. The algal EPA and DHA proportions were lower in the ice-covered CAO than in warmer peripheral shelf seas, which indicates that the paradigm of an inverse correlation of EPA and DHA proportions with temperature may not hold in the Arctic. We found no systematic differences in the summed EPA and DHA proportions of sea ice versus pelagic algae, and in diatoms versus non-diatoms. Overall, the algal EPA and DHA proportions varied up to four-fold seasonally and 10-fold regionally, pointing to strong light and nutrient limitations in the CAO. Where these limitations ease in a warming Arctic, EPA and DHA proportions are likely to increase alongside increasing primary production, with nutritional benefits for a non-ice-associated food web., (© 2023 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

Competing Interests: The authors report no conflicts of interest.

Purpose: Microscopic Draf 2a frontal sinusotomy relied on direct access. However, the modern-day endoscopic approach is hindered by the anterior-posterior dimensions of the frontal recess. The nasofrontal beak, angled endoscopes, and variable frontal recess anatomy make the surgery challenging. Carolyn's window frontal sinusotomy removes the limitation of anterior-posterior dimensions and is an endoscopic version of the microscopic Draf 2a. This study aims to compare the perioperative outcomes and morbidity from endoscopic direct access Draf 2a compared to angled access Draf 2a., Methods: Consecutive adult patients (> 18 years) seen at a tertiary referral clinic who underwent Draf 2a frontal sinus surgery using either endoscopic direct access (Carolyn's window) or endoscopic angled instrumentation were included. Patients who underwent Carolyn's window were compared to those with angled Draf 2a frontal sinusotomy., Results: One hundred patients (age 51.96 ± 15.85 years, 48.0% female, follow-up 60.75 ± 17.34 months) were included. 44% of patients used Carolyn's window approach. 100% [95% CI 98.2-100%] of patients achieved successful frontal sinus patency. Both groups were comparable for early morbidities (bleeding, pain, crusting, and adhesions) and late morbidities (retained frontal recess partitions). There were no other morbidities in the early and late postoperative periods., Conclusion: The endoscopic direct access Draf 2a, or Carolyn's window, removes the anteroposterior diameter limitation. The frontal sinus patency and early and late surgical morbidities of direct access Draf 2a were comparable with the angled Draf 2a frontal sinusotomy. Surgical modifications, often with drills and bone removal, can be successfully made to enhance access in endoscopic sinus surgery without concern for additional morbidity., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

(N)-Methanocarba adenosine derivatives were structurally modified to target 5-HT 2B serotonin receptors as antagonists, predominantly containing branched N 6 -alkyl groups. N 6 -Dicycloalkyl-methyl groups, including their asymmetric variations, as well as 2-iodo, were found to generally favor 5-HT 2 Rs, while only N 6 -dicyclohexyl-methyl derivative 35 showed weak 5-HT 2A R affinity (K i 3.6 μM). The highest 5-HT 2B R affinities were K i 11-23 nM (N 6 -dicyclopropyl-methyl-2-iodo 11, 2-chloro-5'-deoxy-5'-methylthio 15 and N 6 -((R)-cyclobuty-cyclopropyl-methyl)-2-iodo 43), and K i 73 nM at 5-HT 2C R for 36. Direct comparison of adenine ribosides and their corresponding rigid (N)-methanocarba derivatives (cf. 51 and MRS8099 45) indicated a multifold affinity enhancement with the bicyclic ring system. Compounds 43, 45 and 48 were functional 5-HT 2B R (K B 2-3 nM) and 5-HT 2C R (K B 79-328 nM) antagonists in a G q -mediated calcium flux assay, with 5-HT 2B R functional selectivity ranging from 45- (48) to 113-fold (43). Substantial adenosine receptor (AR) affinity (K i , A 1 AR < K i , A 3 AR < K i , A 2A AR) was still present in this series, suggestive of dual acting compounds: 5-HT 2B antagonist and A 1 AR agonist, potentially useful for treating chronic conditions (fibrosis; pain). Given its affinity (17 nM) and moderate 5-HT 2B R binding selectivity (32-fold vs. 5-HT 2C R, 4-fold vs. A 1 AR), 43 (MRS7925) could potentially be useful for anti-fibrotic therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Masson SAS.)

Objectives: Due to the complexity and variety of the frontal recess and sinus anatomy, traditional Draf 2a frontal sinus surgery is challenging. The thickness of the nasofrontal beak and anterior-posterior dimensions of the frontal recess contribute to this complexity. Carolyn's window technique eliminates the limitation of anterior-posterior depth to facilitate a Draf 2a frontal sinusotomy. The approach is a 0° endoscope technique and provides an excellent view of the frontal sinus and recess. We describe Carolyn's window approach to frontal sinus surgery and the perioperative outcomes., Methods: Consecutive adult patients in whom Carolyn's window technique was applied for frontal sinus dissection as part of the endoscopic management of both inflammatory and neoplastic disease were assessed. The primary outcome was frontal sinus patency. Secondary outcomes were surgical morbidity, defined as early (<90 days) or late (>90 days)., Results: Forty-five patients (49.1 ± 17.9 years, 48.9% Female) were assessed. All patients had successful frontal sinus patency (100% [95CI: 92.1%-100%]). Morbidities were adhesion (4.8%), crusting (2.4%), pain (1.2%), and bleeding (1.2%) in the early postoperative period. There were no other morbidities in the early and late postoperative periods., Conclusion: Carolyn's window approach to frontal sinusotomy is a technique that evolves from previously described approaches. Successful frontal sinus patency with very low morbidities is achieved while still working with a 0° endoscope. The "axillectomy" performed simplifies frontal recess surgery by removing the anteroposterior diameter limitation and the dexterity required in angled endoscopy and instrumentation. The inferior-based lateral wall mucosal flap and free mucosal grafting expedite the mucosal healing process. Laryngoscope, 133:2496-2501, 2023., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: The Cavernous Hemangioma Exclusively Endonasal Resection (CHEER) staging system has become the gold standard for outcomes reporting in endoscopic orbital surgery for orbital cavernous hemangiomas (OCHs). A recent systematic review demonstrated similar outcomes between OCHs and other primary benign orbital tumors (PBOTs). Therefore, we hypothesized that a simplified and more comprehensive classification system could be developed to predict surgical outcomes of other PBOTs., Methods: Patient and tumor characteristics as well as surgical outcomes from 11 international centers were recorded. All tumors were retrospectively assigned an Orbital Resection by Intranasal Technique (ORBIT) class and stratified based on surgical approach as either exclusively endoscopic or combined (endoscopic and open). Outcomes based on approach were compared using chi-squared or Fisher's exact tests. The Cochrane-Armitage test for trend was used to analyze outcomes by class., Results: Findings from 110 PBOTs from 110 patients (age 49.0 ± 15.0 years, 51.9% female) were included in the analysis. Higher ORBIT class was associated with a lower likelihood of gross total resection (GTR). GTR was more likely to be achieved when an exclusively endoscopic approach was utilized (p < 0.05). Tumors resected using a combined approach tended to be larger, to present with diplopia, and to have an immediate postoperative cranial nerve palsy (p < 0.05)., Conclusion: Endoscopic treatment of PBOTs is an effective approach, with favorable short-term and long-term postoperative outcomes as well as low rate of adverse events. The ORBIT classification system is an anatomic-based framework that effectively facilitates high-quality outcomes reporting for all PBOTs., (© 2023 ARS-AAOA, LLC.)

Background: Middle meatal antrostomy (MMA) is the traditional intervention for chronic maxillary sinusitis but often fails to correct a nonfunctioning maxillary sinus that has lost its capability for mucociliary clearance. Endoscopic-modified medial maxillectomy (EMMM) can reshape the maxillary sinus and avoid a "sumping" effect, preventing secondary bacterial colonization, encouraging dependent drainage, and promoting effective nasal irrigation., Objectives: We describe a modification of the EMMM surgical technique in patients with recalcitrant maxillary sinusitis and perioperative outcomes., Methods: Consecutive adult patients with nonfunctioning maxillary sinuses managed with EMMM were assessed. Primary outcomes were the resolution of the presenting symptom and the absence of mucostasis. Secondary outcomes were early (<90 days) and late (>90 days) morbidity., Results: Fifty-seven patients (51.7  ±  17.5 years, 56.1% female) were assessed. Fifty-two patients had complete resolution of their presenting symptom (91.2% [95% CI: 80.7-97.1]) and 52 patients had an absence of mucostasis (91.2% [95% CI: 80.7-97.1]). Those with persistent crusting were also those with symptoms. Early morbidities included temporary dysesthesia (3.2%), bleeding (1.1%), and pain (3.2%), with no late morbidities., Conclusion: EMMM is a robust approach for salvaging a nonfunctioning maxillary sinus. The procedure enhances nasal irrigation, supplants mucociliary clearance, and discourages dependent mucus retention.

Adenosine receptor (AR) ligands are being developed for metabolic, cardiovascular, neurological, and inflammatory diseases and cancer. The ease of drug discovery is contingent on the availability of pharmacological tools. Fluorescent antagonist ligands for the human A 2A and A 3 ARs were synthesized using two validated pharmacophores, 1,3-dipropyl-8-phenylxanthine and triazolo[1,5-c]quinazolin-5-yl)amine, which were coupled to eight reporter fluorophores: AlexaFluor, JaneliaFluor (JF), cyanine, and near infrared (NIR) dyes. The conjugates were first screened using radioligand binding in HEK293 cells expressing one of the three AR subtypes. The highest affinities at A 2A AR were K i 144-316 nM for 10, 12, and 19, and at A 3 AR affinity of K i 21.6 nM for 19. Specific binding of JF646 conjugate MRS7774 12 to the HEK293 cell surface A 2A AR was imaged using confocal microscopy. Compound 19 MRS7535, a triazolo[1,5-c]quinazolin-5-yl)amine containing a Sulfo-Cy7 NIR dye, was suitable for A 3 AR characterization in whole cells by flow cytometry (K d 11.8 nM), and its bitopic interaction mode with an A 3 AR homology model was predicted. Given its affinity and selectivity (11-fold vs. A 2A AR, ~ 50-fold vs. A 1 AR and A 2B AR) and a good specific-to-nonspecific binding ratio, 19 could be useful for live cell or potentially a diagnostic in vivo NIR imaging tool and/or therapy targeting the A 3 AR., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

( N )-Methanocarba adenosine derivatives (A 3 adenosine receptor (AR) agonists containing bicyclo[3.1.0]hexane replacing furanose) were chain-extended at N 6 and C2 positions with terminal alkenes for ring closure. The resulting macrocycles of 17-20 atoms retained affinity, indicating a spatially proximal orientation of these receptor-bound chains, consistent with molecular modeling of 12 . C2-Arylethynyl-linked macrocycle 19 was more A 3 AR-selective than 2-ether-linked macrocycle 12 (both 5'-methylamides, human (h) A 3 AR affinities ( K i ): 22.1 and 25.8 nM, respectively), with lower mouse A 3 AR affinities. Functional hA 3 AR comparison of two sets of open/closed analogues in β-arrestin2 and G i/o protein assays showed certain signaling preferences divergent from reference agonist Cl-IB-MECA 1 . The potencies of 1 at all three Gα i isoforms were slightly less than its hA 3 AR binding affinity ( K i : 1.4 nM), while the Gα i1 and Gα i2 potencies of macrocycle 12 were roughly an order of magnitude higher than its radioligand binding affinity. Gα i2 -coupling was enhanced in macrocycle 12 (EC 50 2.56 nM, ∼40% greater maximal efficacy than 1 ). Di-O-allyl precursor 18 cyclized to form 19 , increasing the Gα i1 potency by 7.5-fold. The macrocycles 12 and 19 and their open precursors 11 and 18 potently stimulated β-arrestin2 recruitment, with EC 50 values (nM) of 5.17, 4.36, 1.30, and 4.35, respectively, and with nearly 50% greater efficacy compared to 1 . This example of macrocyclization altering the coupling pathways of small-molecule (nonpeptide) GPCR agonists is the first for potent and selective macrocyclic AR agonists. These initial macrocyclic derivatives can serve as a guide for the future design of macrocyclic AR agonists displaying unanticipated pharmacology., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

Objectives: The aims were to (1) prospectively observe the incidence of bone marrow oedema in asymptomatic adult male domestic professional cricketers during a season and evaluate its relationship to the development of lumbar bone stress injury and (2) further understand the practicalities of implementing a Magnetic Resonance Imaging-based screening program to prevent lumbar bone stress injury in New Zealand cricket., Design: Prospective observational cohort., Methods: Adult male pace bowlers received 6-weekly pre-planned Magnetic Resonance Imaging scans over a single season to determine the presence and intensity of bone marrow oedema in the posterior vertebral arches of the lumbar spine. The participants bowling volume and back pain levels were monitored prospectively., Results: 22 participants (mean age 25.3 years (range 20-32 years)) completed all 4 scans. Ten participants had a prior history of lumbar bone stress injury. Ten participants (45 %, 95 % confidence interval 24-68 %) had bone marrow oedema evident on at least one scan, with 9 (41 %) participants recording a bone marrow oedema intensity ≥ 2 and 5 (23 %) participants demonstrated an intensity ≥ 3. During the study one participant was diagnosed with a lumbar bone stress reaction. No participants developed a lumbar bone stress fracture., Conclusions: Due to the lower incidence of lumbar bone stress injuries in adult bowlers coupled with uncertainty over appropriate threshold values for bone marrow oedema intensity, implementation of a resource intense screening program aimed at identifying adult domestic cricketers at risk of developing a lumbar bone stress injury is not currently supported., Competing Interests: Declaration of interest statement The authors have no conflict of interest to declare. The authors declare that the manuscript submitted to the Journal has not been published elsewhere nor is being considered for publication elsewhere and that the research reported will not be submitted for publication elsewhere until a final decision has been made as to its acceptability by the Journal., (Copyright © 2023 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

Background: Radiologically undifferentiated lesions of the cavernous sinus can pose a diagnostic challenge. Although radiotherapy is the mainstay for treatment of cavernous sinus lesions, histologic diagnosis allows access to a wide variety of alternative treatment modalities. The region is considered a high-risk area for open transcranial surgical access, and the endoscopic endonasal approach presents an alternative technique for biopsy., Methods: A retrospective case series was performed of all patients undergoing endoscopic endonasal biopsy of isolated cavernous sinus lesions at 2 tertiary institutions. The primary outcomes were the percentage of patients in whom a histologic diagnosis was achieved and the proportion of patients in whom therapy differed from radiotherapy alone. Secondary outcomes included preoperative and postoperative 22-item Sino-Nasal Outcome Test symptom scores, as well as perioperative adverse outcomes., Results: Eleven patients underwent endoscopic endonasal biopsy, with a diagnosis achieved in 10 patients. The most common diagnosis was perineural spread of squamous cell carcinoma, followed by perineuroma and single cases of metastatic melanoma, metastatic adenoid cystic carcinoma, mycobacterium lepri infection, neurofibroma, and lymphoma. Six patients had treatments other than radiotherapy, including immunotherapy, antibiotics, corticosteroids, chemotherapy, and observation alone. There was no significant difference in prebiopsy and postbiopsy 22-item Sino-Nasal Outcome Test scores. There was 1 case of epistaxis requiring return to theater for cautery of the sphenopalatine artery and there were no mortalities., Conclusions: In a limited case series, endoscopic endonasal biopsy was safe and effective in obtaining diagnosis for cavernous sinus lesions and had a significant impact on therapeutic decision making., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Endoscopic sinus surgery with a middle meatal antrostomy is a common intervention in the treatment algorithm for maxillary sinus pathologies. However, this procedure has its origins in a time when simple ventilation of the sinus cavity was the primary (and only often) goal of surgery. In some patients, persistent mucociliary dysfunction occurs despite ventilatory surgery. Although the endoscopic modified medial maxillectomy (MMM) was originally described for tumour surgery, it provides a radical yet still functional option to overcome chronic sinus dysfunction., Objective: The goal of this study was to describe the functional status of a post-MMM sinus cavity., Methods: A consecutive series of patients who underwent at least a unilateral MMM by three tertiary rhinologists were retrospectively reviewed. Prospectively collected data included patient demographics (including age, gender, smoking status and comorbidities), disease-specific factors, microbiology, and preoperative patient-reported symptoms based on the 22-item Sinonasal Outcome Test-22 (SNOT-22) and radiology. The primary outcome of the study was the presence of sinus dysfunction, defined by mucostasis or pooling on endoscopic examination at the last follow-up. Secondary outcomes included the need for revision surgery as a result of sinus dysfunction and the improvement in SNOT-22 score., Results: A total of 551 medial maxillectomies (47.0% female, 52.9 ± 16.8 years) were performed. Very few patients experienced post-operative sustained mucostasis following MMM (10.2%) and even fewer required revision surgery (5.0%). Chronic obstructive pulmonary disease (odds ratio (OR) = 6.82, P  < 0.002.) and asthma (OR = 2.48, P  = 0.03) were associated with mucostasis. Patients who underwent an MMM experienced a notable postoperative improvement in SNOT-22 score (45.9 ± 23.7 (pre-op) vs. 23.6 ± 19.4 (post-op); paired t -test, P  < 0.0001)., Conclusion: The MMM, whether performed for access to pathology or with the intent to avoid mucous 'sumping' with the sinus, can provide a long-term functional maxillary sinus cavity with minimal morbidity.

Background: A considerable volume of possible applications of artificial intelligence (AI) in the field of rhinology exists, and research in the area is rapidly evolving., Objective: This scoping review aims to provide a brief overview of all current literature on AI in the field of rhinology. Further, it aims to highlight gaps in the literature for future rhinology researchers., Methods: OVID MEDLINE (1946-2022) and EMBASE (1974-2022) were searched from January 1, 2017 until May 14, 2022 to identify all relevant articles. The Preferred Reporting Items for Systematic Reviews and Meta-analyses Extension for Scoping Reviews checklist was used to guide the review., Results: A total of 2420 results were identified of which 62 met the eligibility criteria. A further 17 articles were included through bibliography searching, for a total of 79 articles on AI in rhinology. Each year resulted in an increase in the number of publications, from 3 articles published in 2017 to 31 articles published in 2021. Articles were produced by authors from 22 countries with a relative majority coming from the USA (19%), China (19%), and South Korea (13%). Articles were placed into 1 of 5 categories: phenotyping/endotyping (n = 12), radiological diagnostics (n = 42), prognostication (n = 10), non-radiological diagnostics (n = 7), surgical assessment/planning (n = 8). Diagnostic or prognostic utility of the AI algorithms were rated as excellent (n = 29), very good (n = 25), good (n = 7), sufficient (n = 1), bad (n = 2), or was not reported/not applicable (n = 15)., Conclusions: AI is experiencing an increasingly significant role in rhinology research. Articles are showing high rates of diagnostic accuracy and are being published at an almost exponential rate around the world. Utilizing AI in radiological diagnosis was the most published topic of research, however, AI in rhinology is still in its infancy and there are several topics yet to be thoroughly explored.

Background: Access to the anterior, lateral, inferior, and inferomedial maxillary sinus has been a limitation of the middle meatal antrostomy. Expanded techniques such as the modified medial maxillectomy provide access to many of these areas but require remucosalization, and crusting can occur during the recovery phase. The prelacrimal approach (PLA) offers direct 0° endoscope access to these areas. Additionally, PLA can preserve the nasolacrimal duct and mucosal coverage., Objectives: We describe the current surgical technique and outcomes of PLA patients., Methods: Consecutive adult patients with pathology addressed by PLA to the maxillary sinus were assessed. The primary outcome was the restoration of the lateral wall, and the secondary outcomes were early (< 90 days) and late morbidity (> 90 days)., Results: Forty patients (52.8 ± 17 years, 62.5% female) were assessed. All patients had successful restoration of the lateral nasal wall (100% [95CI: 91.2%-100%]). The complications reported were primarily dysesthesia (early 10% and late 2.5%)., Conclusion: The PLA provides robust access to the anterior, lateral, inferior, and inferomedial maxilla. PLA offers rapid mucosal recovery while preserving the normal physiology and the lacrimal systems with low morbidity.

COVID-19 disease is associated with progressive accumulation of SARS-CoV-2-specific mRNA, which is recognized by innate immune receptors, such as TLR3. This in turn leads to dysregulated production of multiple cytokines, including IL-6, IFN-γ, CXCL1, and TNF-α. Excessive production of these cytokines leads to acute lung injury (ALI), which consequently compromises alveolar exchange of O 2 and CO 2 . It is therefore of considerable interest to develop novel therapies that reduce pulmonary inflammation and stem production of pro-inflammatory cytokines, potentially for COVID-19 patients that are at high risk of developing severe disease. Purinergic signaling has a central role in fine-tuning the innate immune system, with P2 (nucleotide) receptor antagonists and adenosine receptor agonists having anti-inflammatory effects. Accordingly, we focused here on the potential role of purinergic receptors in driving neutrophilic inflammation and cytokine production in a mouse model of pulmonary inflammation. To mimic the effects of SARS-CoV-2-specific RNA accumulation in mice, we administered progressively increasing daily doses of a viral mimetic, polyinosinic:polycytidylic acid [poly(I:C)] into the airways of mice over the course of 1 week. Some mice also received increasing daily doses of ovalbumin to mimic virus-encoded protein accumulation. Animals receiving both poly(I:C) and ovalbumin displayed particularly high cytokine levels and neutrophilia, suggestive of both innate and antigen-specific, adaptive immune responses. The extent of these responses was diminished by genetic deletion (P2Y 14 R, P2X7R) or pharmacologic modulation (P2Y 14 R antagonists, A 3 AR agonists) of purinergic receptors. These results suggest that pharmacologic modulation of select purinergic receptors might be therapeutically useful in treating COVID-19 and other pulmonary infections., Competing Interests: The authors declare no competing financial interest., (Not subject to U.S. Copyright. Published 2022 by American Chemical Society.)

Background: Nasal endoscopy is increasingly accessible to ENT surgeons. The characteristics of the allergic upper airway are not well recognised., Methodology: MEDLINE (1946-2021), EMBASE (1974-2021), and the Cochrane Library were searched on 16th November 2021 to identify articles that reported endoscopic findings of patients with documented allergy who had undergone nasal endoscopy. The review followed the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy. Meta-analysis was performed by pooling sensitivities and specificities using the hierarchical summary receiver operating characteristics model., Results: A total of 4108 articles were identified, of which 15 manuscripts met the inclusion criteria. The included studies involved 4660 patients who had undergone nasal endoscopy. Middle turbinate (diffuse/polypoid) oedema (sensitivity 58.0%, specificity 84.5%), watery secretions (sensitivity 65.7%, specificity 76.5%), inferior turbinate hypertrophy (sensitivity 86.2%, specificity 32.2%), and unspecified turbinate hypertrophy (sensitivity 82.0%, specificity 42.9%) were identified as the features with the highest predictive value of inhalant allergy., Conclusions: Diffuse or polypoid oedema of the middle turbinate or watery secretions seen on nasal endoscopy can be a useful adjunct in the identification and diagnosis of inhalant allergy. These clinical features should be part of the diagnostic workup for patients that includes a clinical history and surrogate markers of allergic sensitisation from the skin and serum.

Absorbable steroid-eluting sinus implants provide targeted corticosteroid release over a sustained period and are designed to prevent both undesirable adhesion formation and sinus ostia restenosis. Here, we highlight the key evidence of these implants to date and query a group of experts via a Delphi process on the indications and optimal timing for intraoperative or in-office placement of these implants. Six of a total of 12 statements reached consensus and were accepted. Overall, experts largely agree that intraoperative or in-office use of steroid-eluting stents could be considered for patients: (1) who are diabetic or intolerant of oral steroids, (2) undergoing extended frontal sinus surgery, and (3) with recurrent stenosis. Given the lack of expert consensus on other key statements, clinicians should carefully consider these treatment options on a case-by-case basis after shared decision-making., (© 2022 ARS-AAOA, LLC.)

Phosphaturic mesenchymal tumour (PMT) is a rare tumour that occurs in bone or soft tissue and is associated with production of fibroblast growth factor 23 (FGF23) leading to tumor-induced osteomalacia. We report three cases of PMT involving the head and neck that highlight the broad spectrum of clinical and histologic features of PMT. One of these lesions from the hard palate demonstrated an admixture of epithelial and mesenchymal elements, a feature that can pose a diagnostic challenge. The diagnostic utility of immunohistochemistry including FGF23, somatostatin receptor 2A, SATB2, ERG and CD56 is discussed. The biochemical pathway in the development of PMT associated tumor induced osteomalacia and its role in investigations and management of PMT is also described., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The pathophysiology of empty nose syndrome (ENS) remains unclear despite significant research. The pathophysiologic mechanism of ENS was systematically reviewed., Data Sources: MEDLINE and Embase., Review Methods: Data were systematically reviewed for studies that provided original data on pathophysiology., Results: A total of 2476 studies were screened, and 19 met the inclusion criteria: 13 case-control and 6 cross-sectional. Nine pathophysiologic themes were identified.• Demographics: ENS symptoms had no relationship with climatic factors.• Symptomatology: ENS patients demonstrated high symptom severity.• Mental health: Anxiety and depression including hyperventilation were reported in >50% of ENS patients and correlated with ENS symptom severity.• Anatomic features: Structural changes in response to turbinate surgery were similar between ENS and non-ENS patients.• Airflow analysis: Airflow parameters were similar between ENS and non-ENS patients after turbinate surgery. On computational fluid dynamic analysis, differences were found on multiple outcomes.• Diagnostic testing: The menthol detection test was impaired in ENS, and cotton placement in the airway improved ENS symptoms.• Cognitive function: Functional magnetic resonance imaging showed activation in emotional processing area during breathing.• Olfactory function: Subjective impairment was reported in ENS, but quantitative measures were similar to non-ENS patients.• Mucosal physiology/innate immunity: Turbinate histopathology in ENS showed a tissue-remodeling pattern. Nasal nitric oxide level was lower in ENS patients., Conclusion: There is evidence of high comorbid mental health disorders in ENS patients. An abnormal trigeminal-thermoreceptor response may be present in some patients. The influence of altered airflow and the evidence of surgery as the cause for ENS are unclear.

Objective: To determine the range of incidental mucosal changes in a general sinonasally asymptomatic population on radiology., Data Sources: Medline (1996-present) and Embase (1974-present) were searched on March 14, 2020, to identify articles that reported radiological sinus mucosal findings in asymptomatic population groups. Bibliographic search of included studies was conducted to identify additional articles., Review Methods: The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and Cochrane Handbook for Systematic Reviews of Interventions. A comprehensive search strategy was formulated and articles screened to extract data reporting Lund-Mackay (LM) score, presence of mucous retention cysts, and maxillary mucosal thickening. A random-effects model was used in meta-analysis., Results: A total of 950 articles were identified, of which 33 manuscripts met the inclusion criteria. The included studies involved 16,966 sinonasally asymptomatic subjects. The mean LM score was 2.24 (95% CI, 1.61-2.87), and an LM score of ≥4 in 14.71% (95% CI, 6.86-24.82%) was present across all general asymptomatic population groups. Mucous retention cysts were noted in 13% (95% CI, 8.33-18.55%) and maxillary mucosal thickening of ≥2 mm in 17.73% (95% CI, 8.67-29.08%)., Conclusion: The prevalence of incidental mucosal changes in a general asymptomatic population on radiology needs to be considered when making a diagnosis of chronic rhinosinusitis.

Various adenosine receptor nucleoside-like ligands were found to modulate ATP hydrolysis by the multidrug transporter ABCG2. Both ribose-containing and rigidified (N)-methanocarba nucleosides (C2-, N 6 - and 5'-modified), as well as adenines (C2-, N 6 -, and deaza modified), were included. 57 compounds out of 63 tested either stimulated (50) or inhibited (7) basal ATPase activity. Structure-activity analysis showed a separation of adenosine receptor and ABCG2 activities. The 7-deaza modification had favorable effects in both (N)-methanocarba nucleosides and adenines. Adenine 37c (MRS7608) and (N)-methanocarba 7-deaza-5'-ethyl ester 60 (MRS7343) were found to be potent stimulators of ABCG2 ATPase activity with EC 50 values of 13.2 ± 1.7 and 13.2 ± 2.2 nM, respectively. Both had affinity in the micromolar range for A 3 adenosine receptor and lacked the 5'-amide agonist-enabling group (37c was reported as a weak A 3 antagonist, K i 6.82 μM). Compound 60 significantly inhibited ABCG2 substrate transport (IC 50 0.44 μM). Docking simulations predicted the interaction of 60 with 21 residues in the drug-binding pocket of ABCG2., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Masson SAS.)

The A 3 adenosine receptor (A 3 AR) is a target for pain, ischemia, and inflammatory disease therapy. Among the ligand tools available are selective agonists and antagonists, including radioligands, but most high-affinity non-nucleoside antagonists are limited in selectivity to primate species. We have explored the structure-activity relationship of a previously reported A 3 AR antagonist DPTN 9 ( N -[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]nicotinamide) for radiolabeling, including 3-halo derivatives (3-iodo, MRS7907), and characterized 9 as a high -affinity radioligand [ 3 H]MRS7799. A 3 AR K d values were (nM): 0.55 (human), 3.74 (mouse), and 2.80 (rat). An extended methyl acrylate (MRS8074, 19 ) maintained higher affinity (18.9 nM) than a 3-((5-chlorothiophen-2-yl)ethynyl) derivative 20 . Compound 9 had an excellent brain distribution in rats (brain/plasma ratio ∼1). Receptor docking predicted its orthosteric site binding by engaging residues that were previously found to be essential for AR binding. Thus the new radioligand promises to be a useful species-general antagonist tracer for receptor characterization and drug discovery., Competing Interests: The authors declare no competing financial interest., (© 2022 American Chemical Society.)

Following our study of 4'-truncated (N)-methanocarba-adenosine derivatives that displayed unusually high mouse (m) A 3 AR affinity, we incorporated dopamine-related N 6 substituents in the full agonist 5'-methylamide series. N 6 -(2-(4-Hydroxy-3-methoxy-phenyl)ethyl) derivative MRS7618 11 displayed K i (nM) 0.563 at hA 3 AR (∼20,000-fold selective) and 1.54 at mA 3 AR. 2-Alkyl ethers maintained A 3 affinity, but with less selectivity than 2-alkynes. Parallel functional assays of G protein-dependent and β-arrestin 2 (βarr2)-dependent pathways indicate these are full agonists but not biased. Through use of computational modeling, we hypothesized that phenyl OH/OMe groups interact with polar residues, particularly Gln261, on the mA 3 AR extracellular loops as the basis for the affinity enhancement. Although the pharmacokinetics indicated facile clearance of parent O-methyl catechol nucleosides 21 and 31, prolonged mA 3 AR activation in vivo was observed in a hypothermia model, suggested potential formation of active metabolites through demethylation. Selected analogues induced mouse hypothermia following i.p. injection, indicative of peripheral A 3 AR agonism in vivo., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Masson SAS.)

Background: Biologic therapies such as mepolizumab and benralizumab are currently utilised in the treatment of eosinophilic asthma, and are emerging in the management of eosinophilic chronic rhinosinusitis (eCRS). These biologics inhibit the interaction of IL-5 with its receptor, thus impairing cytokine signalling and eosinophil inflammation. Mepolizumab does so by targeting IL-5, whereas benralizumab targets the α chain of the IL-5 receptor. This study compares the sinonasal tissue response to anti-IL-5 biologic therapies in patients with eCRS., Methods: A cross-sectional study of adult eCRS patients who had completed at least 2 cycles of biologic therapy and underwent endoscopic sinus surgery as part of their management were included. Sinonasal mucosal tissue biopsies were obtained intraoperatively and assessed with structured histopathological examination. Comparisons of tissue histopathology outcomes following treatment with mepolizumab or benralizumab were performed., Results: 18 patients (age 49.6 ± 14.2 years, 47% female, 100% co-morbid asthma) were included in this study, comprising 10 patients managed with mepolizumab and 8 patients managed with benralizumab. Even after mepolizumab, the tissue had predominantly eosinophilic inflammation compared to benralizumab (90% v 0%, p < 0.01), which demonstrated a greater lymphoplasmacytic inflammation (10% v 75%, χ 2 (2) = 14.53, p < 0.01). Compared with benralizumab, mepolizumab had increased tissue eosinophil count (100% v 37.5% >10 eosinophils/HPF, τ b  = -8.47, p < 0.001) and more severe subepithelial oedema (80% v 37.5% severe, τ b  = -2.37, p = 0.02)., Conclusion: Tissue histopathologic outcomes reflect the differing mechanism of action of mepolizumab and benralizumab in eCRS. Further analysis at the tissue level will provide further information to guide application of mAbs in type 2 inflammatory diseases.

Genetic selection of pigs over recent decades has sought to reduce carcass fat content to meet consumer demands for lean meat in many countries (e.g., Australia). Due to the impacts of genetic changes, it is unknown whether the carcass fat measures are still responsive to energy intake. Thus, the present experiment aimed to quantify the relationship between tissue composition and dietary energy intake in finisher pigs selected for low carcass backfat. Intact male and female pigs (n = 56 for each sex; Primegro Genetics, Corowa, NSW, Australia) were fed seven different amounts of an amino acid adequate wheat-based diet containing 14.3 MJ digestible energy (DE)/kg to provide the following daily DE intakes- 25.8, 29.0, 32.6, 35.3, 38.5, 41.5, and 44.2 (ad libitum) MJ DE/d for males, and 25.8, 28.9, 32.0, 35.6, 38.3, 40.9, and 44.5 (ad libitum) MJ DE/d for females between 60 and 108 kg live weight. Body composition of anesthetized pigs was measured using the dual energy X-ray absorptiometry (DXA) method when individual pigs reached 108 kg, and protein, fat, and ash deposition rates were calculated. Pigs were slaughtered on the second day post-DXA scan for carcass backfat measurement. The results showed that the carcass backfat thickness (standardized at 83.7 kg carcass) increased by 0.125 mm for every MJ increase in daily DE intake in male pigs (P = 0.004; R2 = 0.130), but carcass backfat of female pigs (standardized at 85.1 kg carcass) was not responsive to daily DE intake. Whole-body fat composition and fat deposition rate increased linearly (both P < 0.01) in male pigs but quadratically (both P < 0.01) in female pigs in response to DE intake. Every MJ increase of daily DE intake increased the rate of daily protein deposition by 3.8 g in intact male pigs (P < 0.001; R2 = 0.781) and by 2.5 g in female pigs (P < 0.001; R2 = 0.643). In conclusion, the selection for low backfat thickness over the last two decades has altered the response of fat deposition and backfat thickness to energy intake, particularly in female pigs. Despite this change, the linear relationship between DE intake and protein deposition rate was maintained in these modern genetics., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A linear route has been used to prepare ( N )-methanocarba-nucleoside derivatives, which serve as purine receptor ligands having a pre-established, receptor-preferred conformation. To introduce this rigid ribose substitute, a Mitsunobu reaction of a [3.1.0]bicyclohexane 5'-trityl intermediate 3 with a nucleobase is typically followed by functional group modifications. We herein report an efficient scalable convergent synthesis for 2-substituted ( N )-methanocarba-adenosines, which were demonstrated to bind to the A 3 adenosine receptor. The adenine moiety was pre-functionalized with 2-thioethers and other groups before coupling to the bicyclic precursor (3) as a key step to facilitate a high yield Mitsunobu product. This new approach provided the ( N )-methanocarba-adenosines in moderate to good yield, which effectively increased the overall yield compared to a linear synthesis and conserved a key intermediate 3 (a product of nine sequential steps). The generality of this convergent synthesis, which is suitable as an optimized preclinical synthetic route, was demonstrated with various 2-thioether and 2-methoxy substituents., Competing Interests: T. E. L. and R. B. P. are employees of Astrocyte Pharmaceuticals Inc. The other authors have no competing interest to declare., (This journal is © The Royal Society of Chemistry.)

Interannual variability in euphausiid (krill) abundance and population structure and associations of those measures with environmental drivers were investigated in an 11-year study conducted in late August-early September 2005-2015 in offshelf waters (bottom depth > 40 m) in Barrow Canyon and the Beaufort Sea just downstream of Distributed Biological Observatory site 5 (DBO5) near Pt. Barrow, Alaska. Statistically-significant positive correlations were observed among krill population structure (proportion of juveniles and adults), the volume of Late Season Melt Water (LMW), and late-spring Chukchi Sea sea ice extent. High proportions of juvenile and adult krill were seen in years with larger volumes of LMW and greater spring sea ice extents (2006, 2009, 2012-2014) while the converse, high proportions of furcilia, were seen in years with smaller volumes of LMW and lower spring sea ice extent (2005, 2007, 2010, 2011, 2015). These different life stage, sea ice and water mass regimes represent integrated advective responses to mean fall and/or spring Chukchi Sea winds, driven by prevailing atmospheric pressure distributions in the two sets of years. In years with high proportions of juveniles and adults, late-spring and preceding-fall winds were weak and variable while in years with high proportions of furcilia, late-spring and preceding-fall winds were strong, easterly and consistent. The interaction of krill life history with yearly differences in the northward transports of krill and water masses along with sea ice retreat determines the population structure of late-summer krill populations in the DBO5 region near Pt. Barrow. Years with higher proportions of mature krill may provide larger prey to the Pt. Barrow area bowhead whale prey hotspot. The characteristics of prey near Pt. Barrow is dependent on krill abundance and size, large-scale environmental forcing, and interannual variability in recruitment success of krill in the Bering Sea., Competing Interests: The authors have declared that no competing interests exist.

Purpose of Review: The application of robotic surgery to anterior skull base disease has yet to be defined despite the potential for improved tumour resection with less morbidity in this region. Complex anatomy and restricted access have limited the development of robotic anterior skull base surgery., Recent Findings: A limited number of transoral robotic surgical anterior skull base procedures have been undertaken; however, there are significant limitations to the utilization of this technology in the anterior skull base. In this article, the advantages, disadvantages and limitations of robotic anterior skull base surgery are discussed. Currently, the major limitation is the size of the robotic endoscope and of the available instrumentation. Technological advancements that provide promise for the future development of robotic anterior skull base surgery are in development, such as single-port robots, flexible instrument systems and miniaturization and growth of minimally invasive platforms., Summary: Although transnasal access to the skull base is not possible with the currently available robotic systems, promising technology does exist and is in development. Robotic anterior skull base surgery promises to provide greater access to skull base disease, improve oncologic results, reduce morbidity and to reduce the ergonomic burden on the surgeon., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: General practitioners (GPs) have some of the highest rates of mortality from COVID-19 among healthcare workers. SARS-CoV-2 has unique properties that place GPs at particular risk., Objective: The aim of this article is to discuss the nose-related features of SARS-CoV-2 that place GPs at risk, and to make recommendations pertinent to the safety and protection of primary healthcare physicians., Discussion: The highest viral load of SARS-CoV-2 is in the nose and nasopharynx. It is often highest early in the illness, before the development of symptoms. Further, SARS-CoV-2 replicates and continues to shed in the nasopharynx long after the virus is no longer detectable in the lower respiratory tract. This places any physician performing examinations on, or procedures involving, the upper respiratory tract at risk for contracting COVID-19. New-onset hyposmia and dysgeusia are indicators for COVID-19 and should be included in screening protocols.