Validated Symptom Outcomes Following Septal Perforation Repair: Application of the NOSE-Perf Scale.

OBJECTIVE: The Nasal Obstruction Symptom Evaluation (NOSE)-Perf scale was developed and validated to measure symptoms associated with nasal septal perforations. This study reports the application of the NOSE-Perf scale to evaluate symptom change following septal perforation repair. METHODS: Patients with NOSE-Perf evaluations ≥6 months following attempted perforation closure from July 2018 to December 2021 utilizing bilateral nasal mucosal flaps with an interposition graft were eligible for study inclusion. Change in NOSE-Perf scores were noted. Patient demographics, perforation size, and concurrent functional procedures were analyzed for impact on symptom outcomes. RESULTS: One-hundred and seventeen patients met the study criteria. Seventy-nine (67.5%) of the patients were female and the mean (range) age at surgery was 47.3 (14-78) years. Repair failure was noted in 7 (6.0%) patients. Mean (SD) preoperative NOSE-Perf score was 25.3 (95% CI, 23.5-27.1) and postoperative score was 7.9 (95% CI, 6.5-9.3). Minimal clinically important difference (MCID) was estimated and greater than 91% of patients had improvement above this threshold. Patient age, perforation size, or concurrent functional procedures did not impact outcomes. Postoperative scores at short (2-4 months), intermediate (5-8 months), and long-term (≥9 months) time periods showed significant improvement (all p < 0.001) compared to preoperative NOSE-Perf scores. CONCLUSION: Significant reduction in nasal symptoms as measured by the NOSE-Perf scale is noted following bilateral mucosal flap repair. Although the nose does not completely normalize following repair, clinically important improvement was noted in at least 91% of patients. The NOSE-Perf scale is positioned to play a role in the standardization of septal perforation evaluation and outcomes assessment. LEVEL OF EVIDENCE: IV Laryngoscope, 2024.

Assessment of a Novel Tool for the Clinical Grading of Nasal Septal Perforation.

BACKGROUND: Nasal septal perforations (NSP) can have a heterogeneous appearance on endoscopic examination with varying degrees of crusting, inflammatory change, and associated septal deviation. The clinical applicability of these findings as contributors to patient symptoms may be enhanced by use of a standardized assessment. METHODS: Video nasal endoscopy recordings were obtained from 40 patients with NSP. Five raters with varied levels of training ranging from a senior resident to an experienced septal perforation surgeon independently reviewed the videos for the following exam findings: crusting, scarring, granulation tissue, septal deviation, and edema. Scoring for each item was reported on a 3-point (0-2) scale, and each reviewer repeated scoring at a 14-day interval. Interrater and intrarater agreement were calculated using Fleiss kappa for each item and the total scores. Additionally, endoscopy scores were correlated with patient-reported NOSE-Perf symptom scores. RESULTS: Interrater agreement for the overall instrument was in the "fair-to-moderate" range with the following interrater agreement for each item: crusting (0.458-0.575), scarring (0.286-0.308), granulation (0.403-0.406), deviation (0.487-0.494), and edema (0.253-0.406). Intrarater agreement was generally "substantial" for individual items as well as the overall instrument (0.688). The NSP endoscopy scores were moderately correlated with NOSE-Perf scores (r = 0.44, p = 0.008). CONCLUSIONS: An endoscopic evaluation of NSP comprising five exam findings has acceptable interrater and intrarater reliability and correlates with patient-reported outcomes. NSP endoscopy may be applied to future clinical studies for characterization of NSP and assessment of treatment outcomes. LEVEL OF EVIDENCE: Level 3 Laryngoscope, 2024.

The clinical presentation of PIT1 positive pituitary neuroendocrine tumor immunonegative for growth hormone, prolactin, and thyroid stimulating hormone with analysis of clinical and immunostaining dissociation.

BACKGROUND: PIT1 is a pituitary transcription factor that is associated with either growth hormone (GH), prolactin (PRL), or thyroid-stimulating hormone (TSH) production. However, PIT1-positive pituitary neuroendocrine tumors (PitNETs) are occasionally immunonegative for GH, PRL, and TSH. This paper describes the clinical presentation of PIT1 positive however immunonegative PitNETs. METHODS: We conducted a retrospective analysis, identifying 228 PIT1-positive PitNET patients between 2017 and 2022. Out of these, ten (4%) tested negative for GH, PRL, and TSH. Functioning PitNETs were defined as those causing hormonal excess symptoms or hormonal overproduction. RESULTS: As for 10 patients immunonegative for all three hormones however PIT1-positive, the mean ( ± standard deviation) age was 46 ± 13 years with 70% women. Six patients exhibited signs of excess GH or PRL, and three had visual problems. Additionally, one patient had secondary hypothyroidism and adrenal insufficiency resulting from the mass effect. All tumors were macroadenoma, with a median volume of 2.1 cm3 (range, 0.8-17.5 cm3). Gross total resection was attained in six patients by trans-sphenoidal surgery. Postoperatively, eight patients experienced clinical improvement: three in vision, two in amenorrhea, two in headache, and one in acromegaly symptoms. Biochemical improvement was observed in six patients, with all experiencing remission in hormonal excess and one showing improvement in secondary hypothyroidism. Stereotactic radiosurgery was performed in three patients. CONCLUSIONS: Patients with functioning PitNETs may exhibit PIT1 staining without GH, PRL, or TSH staining. Hormonally active tumors exist in this patient population; therefore, close endocrine follow-up is necessary despite the lack of staining for GH, PRL, and TSH.

Viruses in chronic rhinosinusitis: a systematic review.

Background: Unlike acute rhinosinusitis (ARS) which is mostly viral in etiology, the role of viruses in chronic rhinosinusitis (CRS) remains unclear. Viruses may play a role in initiation, exacerbations or perpetuate chronic inflammatory responses in the sinonasal mucosa. Research needs to characterize whether viruses are part of the normal sinonasal microbiome, colonizers or pathogenic. Methods: Systematic review of the English literature was conducted. Following databases were searched with an initial search conducted in November 2021 and then updated through June 2023: Ovid Medline (1946 to present), Ovid Embase (1988 to present), Scopus (2004 to present) and Web of Science (1975 to present). MeSH (Medical Subject Headings) terms included: viruses, virus diseases, sinusitis, and rhinovirus. Keywords: virus, viral infection*, sinusitis, rhinovirus, chronic rhinosinusitis, CRS, respiratory virus, respiratory infection*, and exacerbat*. A supplementary search was conducted through September 2023: Ovid Medline (1946 to present), Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) Daily. Keywords used were: virus, viral infection*, sinusitis, chronic rhinosinusitis, CRS, respiratory virus, respiratory infection*, and exacerbat*. Results: Thirty studies on viruses in CRS met inclusion criteria for full review. These included 17 studies on prevalence of virus in CRS, 5 examining probable causes of host susceptibility to viral infections in CRS, and 8 studies examining pathological pathways in viral association of CRS. The prevalence of viruses in nasal specimens of CRS subjects was higher as compared to controls in most studies, though a few studies showed otherwise. Rhinovirus was the most common virus detected. Studies showed that viruses may be associated with persistent hyper-responsiveness in the sinonasal mucosa, susceptibility to bacterial infections, upregulation of genes involved in the immune response and airway remodeling as well as CRS exacerbations. Presence of viruses was also associated with worse symptom severity scores in CRS subjects. Conclusion: Most data show higher presence of viruses in nasal and serum samples of CRS subjects as compared to controls but their exact role in CRS pathophysiology in unclear. Large studies with longitudinal sampling at all disease phases (i.e., prior to disease initiation, during disease initiation, during disease persistence, and during exacerbations) using standardized sampling techniques are needed to definitively elucidate the role of virus in CRS.

Identification, structural, and biophysical characterization of a positive modulator of human Kv3.1 channels.

Voltage-gated potassium channels (Kv) are tetrameric membrane proteins that provide a highly selective pathway for potassium ions (K+) to diffuse across a hydrophobic cell membrane. These unique voltage-gated cation channels detect changes in membrane potential and, upon activation, help to return the depolarized cell to a resting state during the repolarization stage of each action potential. The Kv3 family of potassium channels is characterized by a high activation potential and rapid kinetics, which play a crucial role for the fast-spiking neuronal phenotype. Mutations in the Kv3.1 channel have been shown to have implications in various neurological diseases like epilepsy and Alzheimer's disease. Moreover, disruptions in neuronal circuitry involving Kv3.1 have been correlated with negative symptoms of schizophrenia. Here, we report the discovery of a novel positive modulator of Kv3.1, investigate its biophysical properties, and determine the cryo-EM structure of the compound in complex with Kv3.1. Structural analysis reveals the molecular determinants of positive modulation in Kv3.1 channels by this class of compounds and provides additional opportunities for rational drug design for the treatment of associated neurological disorders.

Combined endoscopic sinus surgery and endonasal septal perforation repair: Symptom outcomes and perforation closure rates.

KEYPOINTS: Combined endoscopic sinus surgery and nasal septal perforation repair is technically feasible. NOSE-Perf is a recently developed patient-reported outcome measure for nasal septal perforation. The decision to perform combined ESS and NSP repair should be made on a case-by-case basis.

Genome-wide Epigenetic Study of Chronic Rhinosinusitis Tissues Reveals Dysregulated Inflammatory, Immunologic and Remodeling Pathways.

BACKGROUND: Epigenetics studies mechanisms such as DNA methylation, histone modifications, non-coding RNAs, and alternative polyadenylation that can modify gene activity without changing the underlying DNA nucleotide base-pair structure. Because these changes are reversible, they have potential in developing novel therapeutics. Currently, seven pharmaceutical agents targeting epigenetic changes are FDA approved and commercially available for treatment of certain cancers. However, studies investigating epigenetics in chronic rhinosinusitis (CRS) have not been undertaken previously in the United States. OBJECTIVES: The goal of this study was to investigate sinonasal DNA methylation patterns in CRS versus controls, to discern environmentally-induced epigenetic changes impacting CRS subjects. METHODS AND RESULTS: Ethmoidal samples from CRS and inferior turbinate mucosal tissue samples from controls without CRS were studied. DNA methylation was studied by Reduced Representation Bisulfite Sequencing. RADMeth® biostatistical package was used to identify differentially methylated regions (DMRs) between CRS and controls. Ingenuity Pathway analysis of DMRs was performed to identify top upstream regulators and canonical pathways. Ninety-three samples from 64 CRS subjects (36 CRSwNP; 28 CRSsNP) and 29 controls were studied. CRS and control samples differed in 13 662 CpGs sites and 1381 DMRs. Top upstream regulators identified included: 1. CRS versus controls: TGFB1, TNF, TP53, DGCR8, and beta-estradiol. 2. CRSwNP versus controls: TGFB1, CTNNB1, lipopolysaccharide, ID2, and TCF7L2. 3. CRSsNP versus controls: MYOD1, acetone, ID2, ST8SIA4, and LEPR. CONCLUSIONS: Differential patterns of methylation were identified between controls and CRS, CRSwNP, and CRSsNP. Epigenetic, environmentally-induced changes related to novel, inflammatory, immunologic, and remodeling pathways appear to affect epithelial integrity, cell proliferation, homeostasis, vascular permeability, and other yet uncharacterized pathways and genes.

Outcomes of Frontal Sinus Stenting With Steroid Impregnated Microsponge Versus Steroid-Eluting Implant.

BACKGROUND: Mometasone-eluting poly-L-lactide-coglycolide (MPLG) is available commercially for frontal sinus ostium (FSO) stenting. An alternative chitosan polymer-based drug delivery microsponge is also available at a lower cost per unit. OBJECTIVE: To compare the outcomes of MPLG stents versus triamcinolone-impregnated chitosan polymer (TICP) microsponge in frontal sinus surgery. METHODS: Patients who underwent endoscopic sinus surgery from December 2018 to February 2022 were reviewed to identify those with the intraoperative placement of TICP microsponge or MPLG stent in the FSO. FSO patency was evaluated by endoscopy at follow-up. Twenty-two-item sinonasal outcome test (SNOT-22) was also recorded, and complications were noted. RESULTS: A total of 68 subjects and 96 FSOs were treated. TICP was first used in August 2021 and MPLG in December 2018. MPLG placement in a Draf 3 cavity was excluded since TICP had not been used during Draf 3 procedure. Both cohorts (TICP 20 subjects, 35 FSOs; MPLG 26 subjects, 39 FSOs) had similar clinical characteristics. At a mean total follow-up of 249.2 days for TICP and 490.4 days for MPLG, FSO patency was 82.9% and 87.1%, respectively (P = .265). At an equivalent follow-up of 130.6 days in TICP and 154.0 days in MPLG, patency was 94.3% and 89.7%, respectively (P = .475). Both groups showed significant reductions in SNOT-22 (P < .001). MPLG demonstrated crusting within the FSO at 1 month (none in TICP). CONCLUSION: FSO patency for both stents was similar, although TICP had significantly lower costs per unit. Additional comparative trials may be helpful for guiding clinicians on the appropriate clinical situations for the use of these devices.

Autologous Interposition Grafts for Mucosal Flap Septal Perforation Repair.

Background: Nasal septal perforation repair is commonly attempted utilizing bilateral nasal mucosal flaps supported with an interposition graft. Objectives: To compare the failure rates for bilateral flap repairs utilizing four different autologous interposition grafts. Methods: This is a retrospective review of a single surgeon's bilateral flap perforation repairs supported with an autologous interposition graft. Study inclusion over the 18-year review period required at least one examination 1 month after surgery. Repair failure rates were calculated and compared for each graft type, and logistic regression was performed for multivariate analysis. Results: For the 356 study patients, median (range) age was 51 years (14-81) and 63.0% were women. Mean (range) perforation length was 13.9 mm (1-45). Median (range) at last follow-up was 11.2 months (1-192). Graft types used (percentage of patients and failure rate) were temporalis fascia (58.7/4.4), septal cartilage (23.3/7.3), auricular perichondrium (13.8/4.1), and septal bone (4.2/6.7) (p > 0.05). Conclusion: There was no significant difference in bilateral mucosal flap perforation repair failure rate when either a temporalis fascia, septal cartilage, auricular perichondrium, or septal bone interposition graft was used.

Septal Perforation Repair Quality of Life Outcomes Using the Revised 15-item Glasgow Benefit Inventory.

BACKGROUND: The 18-item Glasgow Benefit Inventory (GBI) has been widely used to measure patient general health response to otorhinolaryngologic and facial plastic interventions. The GBI was recently reorganized into 15 questions with 5 sub-scale factors (GBI-5F) to improve its utility. Application of the GBI-5F to septal perforation treatments may improve our understanding of quality of life outcomes. METHODOLOGY/PRINCIPAL: The GBI was given to patients seen from August 2018 through October 2021 who were at least 6 months postoperative attempted perforation surgical closure using bilateral nasal mucosal flaps with an interposition graft. Original GBI and GBI-5F scores were computed and subgroup analysis performed in this retrospective medical record review. RESULTS: Of the 98 patients (mean age 45.5 years) who met study criteria, 65 were female. Mean perforation length was 12.9, and height 9.7 mm. The mean postoperative time to GBI completion was 12.7 months. Highest GBI-5F scores were noted in the Quality of Life factor, followed by Self-confidence and Social Involvement. Females reported significantly higher scores than men. Total GBI scores were similar to those recorded for other rhinologic procedures. CONCLUSIONS: The GBI-5F provides measurable insight into patient quality of life benefit following septal perforation repair.

Outcomes of limited versus extensive surgery for chronic rhinosinusitis: A systematic review and meta-analysis.

KEY POINTS: There is no consensus on the extent of appropriate surgery for chronic rhinosinusitis (CRS), particularly CRS without polyps (CRSsNP). There is wide heterogeneity in the definition of "limited" and "extensive" endoscopic sinus surgery (ESS). Studies on the appropriate extent of surgery for CRS are needed.

Biological sex as a modulator in rhinologic anatomy, physiology, and pathology: A scoping review.

BACKGROUND: Biological sex is increasingly recognized as a critical variable in health care. The authors reviewed the current literature regarding sex-based differences in rhinology to summarize the data and identify critical knowledge gaps. METHODS: A scoping review was conducted. Publications reporting sex-based differences in anatomy, physiology, and pathology focusing on disease prevalence, disease burden, and outcomes in rhinology were identified. RESULTS: Seventy-five relevant manuscripts were identified. While paranasal sinuses are of similar size at birth, they become larger in males leading to differences in ostium location. Females outperform males in olfactory identification but only in the 18- to 50-year age group. Estrogen and progesterone administration can impact muscarinic and α1 -adrenergic nasal mucosa receptor density. Chronic rhinosinusitis (CRS) and CRS without nasal polyps are more prevalent in females while CRS with nasal polyps is more prevalent in males. CRS symptom burden is higher in females before and after endoscopic sinus surgery; however, no difference in endoscopic sinus surgery utilization was found based on sex. Allergic rhinitis is more common in males before puberty and in females after puberty. Epistaxis is more prevalent in males and postmenopausal females compared with premenopausal females, perhaps from differences in sex-hormonal and hypertension status. In nasopharyngeal carcinoma, the incidence of sinus abnormalities was higher in males than females. CONCLUSIONS: Although many sex-based differences exist in rhinology, further research is necessary to offer evidence-based treatment guidelines. Gonadal hormones should be studied as a therapeutic in rhinologic pathology as baseline physiologic differences exist such as those found in nasal mucosa receptor density.

Presenting Symptomatology for Patients With Nasal Septal Perforation: Application of the NOSE-Perf Scale.

OBJECTIVE: To objectively identify and quantitate presenting nasal symptoms in patients with a septal perforation using the validated NOSE-Perf scale. STUDY DESIGN: Case series retrospective review. METHODS: The medical records from August 2018 through January 2022 of patients at a tertiary care academic center with a septal perforation, and who completed the NOSE-Perf questionnaire, were reviewed. Perforation symptoms were identified and quantified using the 12-item NOSE-Perf scale (score range 0-48). NOSE-Perf findings were correlated to patient demographics, perforation etiology, and perforation length. NOSE-Perf scores of patients who pursued treatment were compared with those who did not. RESULTS: NOSE-Perf data were collected from 202 patients. Nasal crusting was noted in 94.1% of patients and was the most severe symptom reported (mean 2.9 of 4.0). Nasal congestion, difficulty breathing, and nasal obstruction followed in prevalence and severity. The mean total NOSE-Perf score was 23.7. Linear regression analysis demonstrated a weakly negative association of NOSE-Perf score with patient age and weakly positive association with increasing perforation length. NOSE-Perf scores were significantly higher in women and in patients pursuing treatment. CONCLUSION: This is the first study to use the validated NOSE-Perf scale to objectively characterize and establish baseline septal perforation symptomatology. The NOSE-Perf scale can play a role in the standardization of perforation evaluation and treatment outcomes assessment. Laryngoscope, 133:1315-1320, 2023.

Unified Airway Disease: Future Directions.

Unified airway disease describes the shared epidemiologic and pathophysiologic relationship among the chronic inflammatory diseases of the upper and lower airways including allergic rhinitis, chronic rhinosinusitis, asthma, and chronic otitis media. This concept proposes that these diseases are manifestations of a single inflammatory process and require an integrated diagnostic and therapeutic approach to achieve global disease control. Future directions to further establish this entity should focus on pathophysiology, diagnostic markers, flora microbes with particular emphasis on fungi, the role of type 3 inflammation, and targeted therapeutics including biologics, JAK inhibitors, and synthetic peptides.

Unified Airway Disease: Genetics and Epigenetics.

Although unified airway disease (UAD) may have heritable components, genetic changes involving coexistent chronic rhinosinusitis (CRS) are not well understood. Genetic predisposition is stronger in patients with CRS with nasal polyps compared with those without nasal polyps (CRSsNP). Genetic factors account for 25% to 80% of asthma risk and 90% of allergic rhinitis risk but risk contributions are not well described for CRS. Susceptibility genes identified in coexistent CRS-asthma relate to innate and adaptive immunity, cytokine signaling, tissue remodeling, arachidonic acid metabolism, and other proinflammatory pathways. Non-type 2 UAD such as CRS-bronchitis/bronchiectasis and CRSsNP are currently inadequately characterized.

Avoiding bias in artificial intelligence.

Artificial intelligence (AI) is ubiquitous and expanding, and the healthcare industry has rapidly adopted AI and machine learning for numerous applications. It is essential to understand that AI is not immune to the biases that impact our clinical and academic work, and in fact may inadvertently amplify rather than reduce them. As we harness the power of AI, it is our obligation to our patients to ensure that we address these concerns. We must take responsibility for proactive stewardship to protect against bias, not only for new AI algorithms, but also for our research studies that may one day provide data for those algorithms.