Background: Olfactory dysfunction is a common symptom of chronic rhinosinusitis (CRS). We previously identified several cytokines potentially linked to smell loss, potentially supporting an inflammatory etiology for CRSassociated olfactory dysfunction. In the current study we sought to validate pa erns of olfactory dysfunction in CRS using hierarchical cluster analysis, machine learning algorithms, and multivariate regression.Methods: CRS patients undergoing functional endoscopic sinus surgery were administered the Smell Identification Test (SIT) preoperatively. Mucus was collected from the middle meatus using an absorbent polyurethane sponge and 17 inflammatory mediators were assessed using a multiplexed flow-cytometric bead assay. Hierarchical cluster analysis was performed to characterize inflammatory patterns and their association with SIT scores. The random forest approach was used to identify cytokines predictive of olfactory function. Results:One hundred ten patients were enrolled in the study. Hierarchical cluster analysis identified 5 distinct CRS clusters with statistically significant differences in SIT scores observed between individual clusters (p < 0.001). A majority of anosmic patients were found in a single cluster, which was additionally characterized by nasal polyposis (100%) and a high incidence of allergic fungal rhinosinusitis (50%) and aspirin-exacerbated respiratory disease (AERD) (33%). A random forest approach identified a strong association between olfaction and the cytokines interleukin (IL)-5 and IL-13. Multivariate modeling identified AERD, computed tomography (CT) score, and IL-2 as the variables most predictive of olfactory function. Conclusion:Olfactory dysfunction is associated with specific CRS endotypes characterized by severe nasal polyposis, tissue eosinophilia, and AERD. Mucus IL-2 levels, CT score, and AERD were independently associated with smell loss. C 2018 ARS-AAOA, LLC. How to Cite thisArticle: Morse JC, Shilts MH, Ely KA, et al. Pa erns of olfactory dysfunction in chronic rhinosinusitis identified by hierarchical cluster analysis and machine learning algorithms. Int Forum Allergy Rhinol. 2019;9:255-264.O lfactory dysfunction is among the most common symptoms of chronic rhinosinusitus (CRS) with a prevalence of between 30% and 80%. 1, 2 Unfortunately, the etiology of CRS-associated olfactory dysfunction remains poorly understood. Olfactory loss in CRS has previously been attributed to an inability of odorants to effectively reach the olfactory cleft, due either to structural abnormalities or presence of nasal polyps. 3, 4 Recent research has suggested that sinonasal inflammation may directly or indirectly affect olfactory neurons and olfactory function. 5 In animal models, certain cytokines have the ability to adversely affect olfactory neuron function, turnover, and regeneration. 5-8 An association between olfactory cleft cytokine levels and olfactory function has been partially

The goal of this study was to identify the cellular mechanisms responsible for cardiac dysfunction in endotoxemic mice. We aimed to differentiate the roles of cGMP [produced by soluble guanylyl cyclase (sGC)] versus oxidative posttranslational modifications of Ca(2+) transporters. C57BL/6 mice [wild-type (WT) mice] were administered lipopolysaccharide (LPS; 25 μg/g ip) and euthanized 12 h later. Cardiomyocyte sarcomere shortening and Ca(2+) transients (ΔCai) were depressed in LPS-challenged mice versus baseline. The time constant of Ca(2+) decay (τCa) was prolonged, and sarcoplasmic reticulum Ca(2+) load (CaSR) was depressed in LPS-challenged mice (vs. baseline), indicating decreased activity of sarco(endo)plasmic Ca(2+)-ATPase (SERCA). L-type Ca(2+) channel current (ICa,L) was also decreased after LPS challenge, whereas Na(+)/Ca(2+) exchange activity, ryanodine receptors leak flux, or myofilament sensitivity for Ca(2+) were unchanged. All Ca(2+)-handling abnormalities induced by LPS (the decrease in sarcomere shortening, ΔCai, CaSR, ICa,L, and τCa prolongation) were more pronounced in mice deficient in the sGC main isoform (sGCα1(-/-) mice) versus WT mice. LPS did not alter the protein expression of SERCA and phospholamban in either genotype. After LPS, phospholamban phosphorylation at Ser(16) and Thr(17) was unchanged in WT mice and was increased in sGCα1(-/-) mice. LPS caused sulphonylation of SERCA Cys(674) (as measured immunohistochemically and supported by iodoacetamide labeling), which was greater in sGCα1(-/-) versus WT mice. Taken together, these results suggest that cardiac Ca(2+) dysregulation in endotoxemic mice is mediated by a decrease in L-type Ca(2+) channel function and oxidative posttranslational modifications of SERCA Cys(674), with the latter (at least) being opposed by sGC-released cGMP.

Background: Potential effects of aging on chronic rhinosinusitis (CRS) pathophysiology have not been well defined, but may have important ramifications given a rapidly aging U.S. and world population. Objective:The goal of the current study was to determine whether advanced age is associated with specific inflammatory CRS endotypes or immune signatures.Methods: Seventeen mucus cytokines and inflammatory mediators were measured in 147 CRS patients. Hierarchical cluster analysis was used to identify and characterize inflammatory CRS endotypes as well as determine whether age was associated with specific immune signatures.Results: A CRS endotype with a pro-inflammatory, neutrophilic immune signature was enriched with older patients. In the overall cohort, patients 60 years and older had elevated mucus levels of IL-1β, IL-6, IL-8, and TNF-α when compared to their younger counterparts.

IMPORTANCE Numerous techniques are used for septal perforation repair, yet success rates remain variable. Few studies have evaluated the effectiveness of interposition grafts of polydioxanone plates combined with a temporoparietal fascia graft for septal perforation repair.OBJECTIVE To investigate and describe the use of interposition grafts of polydioxanone plates combined with a temporoparietal fascia graft for septal perforation repair and the expansion of this technique to patients with more challenging comorbidities, including granulomatosis with polyangiitis. DESIGN, SETTING, AND PARTICIPANTSA retrospective medical record review was performed of patients who underwent septal perforation repair using interposition grafts of polydioxanone plates combined with a temporoparietal fascia graft from

Background Sinonasal teratocarcinosarcoma (SNTCS) is a rare malignancy of the anterior skull base with only 127 cases described in the English literature. Given the rarity of this tumor, new cases and analysis of published reports may assist in future management of SNTCS. Objectives 1) Describe findings from a systematic review of all available literature for malignant SNTCS including the clinical presentation, treatment modalities and outcomes. 2) Present two new cases of this rare anterior skull base tumor. 3) Compare treatment outcomes with respect to recurrence and mortality. Methods A systematic review of all English literature available in 2 comprehensive databases was conducted by two independent reviewers using PRISMA guidelines. 85 publications were identified. Each case was reviewed for demographics, treatment and survival, and aggregate treatment outcomes were compared using Kaplan-Meier analysis. Results A total of 64 articles meeting inclusion criteria were reported in the literature between 1977-2018. This represented a total of 127 patients, with a strong male predominance (83%) and mean age of 50 years (range 10–82). Mean follow-up was 21 months. Recurrence rate was 38%, with mean survival at 2 years of 55%. Almost all patients underwent surgery as a primary treatment modality (90%). The majority of cases were treated with multimodal therapy, with 55% receiving surgery and radiation and 20% receiving surgery with adjuvant chemoradiation. Kaplan-Meier analysis demonstrated a significant survival advantage for patients treated with combined therapy compared to surgery alone (p < 0.001) but did not show differences in recurrence (p = 0.085). Conclusion Two-year survival rates for SNTCS are 55%. Multimodality treatment outcomes appear to be superior to surgery alone based on the published data of this rare skull base tumor, although heterogeneity of treatment methods and reporting bias limits the generalizability of these findings.

The substrate for ribosomes actively engaged in protein synthesis is a ternary complex of elongation factor Tu (EF-Tu), aminoacyl-tRNA (aa-tRNA), and GTP. EF-Tu plays a critical role in mRNA decoding by increasing the rate and fidelity of aa-tRNA selection at each mRNA codon. Here, using three-color single-molecule fluorescence resonance energy transfer imaging and molecular dynamics simulations, we examine the timing and role of conformational events that mediate the release of aa-tRNA from EF-Tu and EF-Tu from the ribosome after GTP hydrolysis. Our investigations reveal that conformational changes in EF-Tu coordinate the rate-limiting passage of aa-tRNA through the accommodation corridor en route to the peptidyl transferase center of the large ribosomal subunit. Experiments using distinct inhibitors of the accommodation process further show that aa-tRNA must at least partially transit the accommodation corridor for EF-Tu⋅GDP to release. aa-tRNAs failing to undergo peptide bond formation at the end of accommodation corridor passage after EF-Tu release can be reengaged by EF-Tu⋅GTP from solution, coupled to GTP hydrolysis. These observations suggest that additional rounds of ternary complex formation can occur on the ribosome during proofreading, particularly when peptide bond formation is slow, which may serve to increase both the rate and fidelity of protein synthesis at the expense of GTP hydrolysis.

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Background Sepsis-induced cardiomyopathy (SIC) is thought to be the result of detrimental effects of inflammatory mediators on cardiac muscle. Here we studied the effects of prolonged (24 ± 4 h) exposure of adult rat ventricular myocytes (ARVM) to bacterial lipopolysaccharide (LPS) and inflammatory cytokines tumor necrosis factor (TNF) and interleukins-1 (IL-1) and -6 (IL-6). Materials and methods We measured sarcomere shortening (SS) and cellular calcium (Ca2+) transients (ΔCai, with fura-2AM) in isolated cardiomyocytes externally paced at 5Hz at 37 °C. Results SS decreased after incubation with LPS (100 µg/ml), IL-1 (100 ng/ml) and IL-6 (30 ng/ml), but not with lesser doses of these mediators, or TNF (10 –100 ng/ml). A combination of LPS (100 µg/ml), TNF, IL-1 and IL-6 (each 100 ng/ml; i.e. “Cytomix-100”) induced a maximal decrease in SS and ΔCai. Sarcoplasmic reticulum (SR) Ca2+ load (CaSR, measured with caffeine) was unchanged by Cytomix-100, however, SR fractional release (ΔCai/CaSR) was decreased. Underlying these effects, Ca2+ influx into the cell (via L-type Ca2+ channels) and Ca2+ extrusion via Na+/Ca2+ exchange were decreased by Cytomix-100. SR Ca2+ pump (SERCA) was not affected. Conclusions Prolonged exposure of ARVM to a mixture of LPS and inflammatory cytokines inhibits cell contractility. The effect is mediated by the inhibition of Ca2+ influx via LTCC, and partially opposed by the inhibition of Na+/Ca2+ exchange. Since both mechanisms are commonly seen in animal models of SIC, we conclude that prolonged challenge with Cytomix-100 of ARVM may represent an accurate in vitro model for SIC.