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Background: Passive administration of SARS-CoV-2 neutralizing monoclonal antibodies (mAbs), such as CAS + IMD (Casirivimab + Imdevimab) antibody cocktail demonstrated beneficial effects on clinical outcomes in hospitalized patients with COVID-19 who were seronegative at baseline and outpatients. However, little is known about their impact on the host immunophenotypes., Methods: We conducted an immunoprofiling study in 46 patients from a single site of a multi-site trial of CAS + IMD in hospitalized patients. We collected longitudinal samples during October 2020 ∼ April 2021, prior to the emergence of the Delta and Omicron variants and the use of COVID-19 vaccines. All collected samples were analyzed without exclusion and post-hoc statistical analysis was performed. We examined the dynamic interplay of CAS + IMD with host immunity applying dimensional reduction approach on plasma proteomics and high dimensional flow cytometry data., Findings: Using an unbiased clustering method, we identified unique immunophenotypes associated with acute inflammation and disease resolution. Compared to placebo group, administration of CAS + IMD accelerated the transition from an acute inflammatory immunophenotype, to a less inflammatory or "resolving" immunophenotype, as characterized by reduced tissue injury, proinflammatory markers and restored lymphocyte/monocyte imbalance independent of baseline serostatus. Moreover, CAS + IMD did not impair the magnitude or the quality of host T cell immunity against SARS-CoV-2 spike protein., Interpretation: Our results identified immunophenotypic changes indicative of a possible SARS-CoV-2 neutralizing antibodies-induced anti-inflammatory effect, without an evident impairment of cellular antiviral immunity, suggesting that further studies of Mabs effects on SAS-CoV-2 or other viral mediated inflammation are warranted., Funding: Regeneron Pharmaceuticals Inc and federal funds from the Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority, under OT number: HHSO100201700020C., Competing Interests: Declaration of interests B.W., J.G., P.P, Q.W., C.L., M.F.W., E.C., S.C.H., A.T.H., S.K., G.D.K., B.J.M., C.D.P., J.D.H., M.A.S., D.S. are employees of Regeneron Pharmaceuticals, Inc. E.M.O is former employee of Regeneron. E.M. (Eleftherios Mylonakis) received fundings from Regeneron Pharmaceuticals, SciClone Pharmaceuticals, Pfizer, Chemic Labs/KODA Therapeutics, Cidara, and Leidos Biomedical Research Inc./NCI, NIH/NIAID, NIH/NIGMS, and BARDA., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Nasal epithelial cells are important regulators of barrier function and immune signaling; however, in allergic rhinitis (AR) these functions can be disrupted by inflammatory mediators. We aimed to better discern AR disease mechanisms using transcriptome data from nasal brushing samples from individuals with and without AR., Methods: Data were drawn from a feasibility study of individuals with and without AR to Timothy grass and from a clinical trial evaluating 16 weeks of treatment with the following: dupilumab, a monoclonal antibody that binds interleukin (IL)-4Rα and inhibits type 2 inflammation by blocking signaling of both IL-4/IL-13; subcutaneous immunotherapy with Timothy grass (SCIT), which inhibits allergic responses through pleiotropic effects; SCIT + dupilumab; or placebo. Using nasal brushing samples from these studies, we defined distinct gene signatures in nasal tissue of AR disease and after nasal allergen challenge (NAC) and assessed how these signatures were modulated by study drug(s)., Results: Treatment with dupilumab (normalized enrichment score [NES] = -1.73, p = .002) or SCIT + dupilumab (NES = -2.55, p < .001), but not SCIT alone (NES = +1.16, p = .107), significantly repressed the AR disease signature. Dupilumab (NES = -2.55, p < .001), SCIT (NES = -2.99, p < .001), and SCIT + dupilumab (NES = -3.15, p < .001) all repressed the NAC gene signature., Conclusion: These results demonstrate type 2 inflammation is an important contributor to the pathophysiology of AR disease and that inhibition of the type 2 pathway with dupilumab may normalize nasal tissue gene expression., (© 2024 Regeneron Pharmaceuticals Inc and The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

This retrospective evaluation of surgical outcomes for hyomandibular suspension when performed with uvulopalatopharyngoplasty (UPPP) for the treatment of obstructive sleep apnea (OSA). Thirty-nine patients with moderate-to-severe OSA were treated with hyoid myotomy and suspension and uvulopalatopharyngoplasty. Patients underwent hyoid advancement and suspension to the mandible (Encore System) with either staged or concurrent UPPP. The primary outcome was a successful surgical result, defined as an apnea hypopnea index (AHI) lower than 20, and a 50% or greater decline in AHI on postoperative polysomnography. Successful surgical results were achieved in 30 (76.9%) out of 39 patients. The mean preoperative AHI improved 69.2% from 49.9 ± 25.6 to 15.4 ± 14.9 ( P < .001) postoperatively. All patients reported clinical improvement of symptoms. There were 4 wound complications and one infection requiring removal of hardware. For patients with multilevel obstructive sleep apnea, hyoid advancement and suspension to the mandible appears efficacious when performed in conjunction with uvulopalatopharyngoplasty.

Objective: To examine if age, sex, body mass index (BMI), neck circumference, or apnea-hypopnea index can predict whether a patient will demonstrate velopharyngeal complete circumferential (CC) collapse on drug-induced sleep endoscopy (DISE)., Study Design: Single-center retrospective review at The Ohio State Wexner Medical Center of 289 patients between March 2014 and June 2020., Setting: Quaternary care hospital., Methods: Patient characteristic and DISE information was extracted from charts and summarized with mean and standard deviation for continuous variables and count and percentage for categorical. CC collapse and patient characteristic associations were explored: 2-sample t test for continuous and chi-square test for categorical. Classification and regression tree (CART) analysis with 3-fold cross-validation was employed to search for the best CC collapse predictors., Results: Male and female BMI and female neck circumference were correlated to velopharyngeal CC collapse, with BMI more strongly correlated. CART analysis for males showed that a BMI ≤34.8 kg/m 2 is associated with an 89.4% chance of not demonstrating velopharyngeal CC collapse vs 48% for BMI >34.8 (area under the curve [AUC] = 0.705; AUC >0.7 is acceptable). For females, the CART analysis showed that a BMI ≤36.4 is associated with a 98.4% of not demonstrating velopharyngeal CC collapse vs 30.8% for BMI >36.4 (AUC = 0.73). For females, a neck circumference ≤38.05 cm is associated with a 100% chance of not demonstrating velopharyngeal CC collapse vs 18.4% for >38.05 cm (AUC = 0.72)., Conclusion: The BMI values for males and females and the female neck circumference values established by the CART model may accurately predict DISE anatomy and possible candidacy for hypoglossal nerve stimulation.

IgA plays an important early neutralizing role after SARS-CoV-2 infection. Systemically administered vaccines typically produce an IgM/IgG predominant response. We evaluated the serum anti-spike (anti-S) IgG, anti-nucleocapsid (anti-N) IgG and anti-S IgA response following vaccination against SARS-CoV-2 in a cohort of first-responders. Among the 378 completely vaccinated participants, 98% were positive for anti-S IgG and 96% were positive for anti-S IgA. Nine percent were positive for anti-N IgG suggesting prior exposure to SARS-CoV-2. No statistically significant difference was seen in IgA response based on prior evidence infection (p = 0.18). Ninety-eight of those receiving the Moderna vaccine (98%) were positive for anti-S IgA as compared to 91% of those who received the Pfizer vaccine (p = 0.0009). The high proportion of participants observed to have a positive anti-S IgA response after vaccination suggests that the vaccines elicit a systemic response characterized by elevated levels of both IgG and IgA., (© 2022. The Author(s).)

Study Objectives: Untreated obstructive sleep apnea (OSA) is associated with excessive daytime sleepiness, decreased quality of life, and cardiovascular disease. Positive airway pressure is the first-line therapy for OSA; however, adherence is difficult. Upper airway stimulation is a Food and Drug Administration-approved treatment of OSA. The objective of this study was to evaluate for a difference in treatment efficacy and adherence of upper airway stimulation therapy for OSA between individuals who are White and non-White using data from the ADHERE registry., Methods: ADHERE registry is a multicenter prospective study of real-world experience of upper airway stimulation for treatment of OSA in the United States and Europe. Propensity score matching was used to create a balanced dataset between the White and non-White groups. t -Tests at a significance level of 5% were used to compare numeric values between groups., Results: There were 2,755 participants of the ADHERE registry: 27 were excluded due to not having a race identified, 125 participants identified as non-White, 2,603 identify as White, and 27 did not provide race information. Propensity score matching was used to select 110 participants, with 55 White and 55 non-White for the noninferiority analysis. We did not find a difference in adherence, treatment apnea-hypopnea index, changes in Epworth Sleepiness Scale score, or clinical global impression after intervention score between White and non-White individuals., Conclusions: Our study found that there was no statistically significant difference in adherence or efficacy with upper airway stimulation therapy between White and non-White individuals. However, the percent of non-White people implanted is low, which suggests a need to expand access to this therapy for non-White populations with OSA who cannot tolerate positive airway pressure therapy., Citation: Khan M, Stone A, Soose RJ, et al. Does race-ethnicity affect upper airway stimulation adherence and treatment outcome of obstructive sleep apnea? J Clin Sleep Med . 2022;18(9):2167-2172., (© 2022 American Academy of Sleep Medicine.)

Objectives/hypothesis: To provide the ADHERE registry Upper Airway Stimulation (UAS) outcomes update, including analyses grouped by body mass index (BMI) and therapy discomfort., Study Design: Prospective observational study., Methods: ADHERE captures UAS outcomes including apnea-hypopnea index (AHI), Epworth sleepiness scale (ESS), therapy usage, patient satisfaction, clinician assessment, and safety over a 1-year period. BMI ≤32 kg/m 2 (BMI 32 ) and 32 < BMI ≤35 kg/m 2 (BMI 35 ) group outcomes were examined., Results: One thousand eight hundred forty-nine patients enrolled in ADHERE, 1,019 reached final visit, 843 completed the visit. Significant changes in AHI (-20.9, P < .0001) and ESS (- 4.4, P < .0001) were demonstrated. Mean therapy usage was 5.6 ± 2.2 hr/day. Significant therapy use difference was present in patients with reported discomfort versus no discomfort (4.9 ± 2.5 vs. 5.7 ± 2.1 hr/day, P = .01). Patients with discomfort had higher final visit mean AHI versus without discomfort (18.9 ± 18.5 vs. 13.5 ± 13.7 events/hr, P = .01). Changes in AHI and ESS were not significantly different. Serious adverse events reported in 2.3% of patients. Device revision rate was 1.9%. Surgical success was less likely in BMI 35 versus BMI 32 patients (59.8% vs. 72.2%, P = .02). There was a significant therapy use difference: 5.8 ± 2.0 hr/day in BMI 32 versus 5.2 ± 2.2 hr/day in BMI 35 (P = .028)., Conclusions: Data from ADHERE demonstrate high efficacy rates for UAS. Although surgical response rate differs between BMI 32 and BMI 35 patient groups, the AHI and ESS reduction is similar. Discomfort affects therapy adherence and efficacy. Thus, proper therapy settings adjustment to ensure comfort is imperative to improve outcomes., Level of Evidence: 4 Laryngoscope, 131:2616-2624, 2021., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

The objective of our study was to assess the relationship between postoperative opioid prescribing patterns and opioid consumption among patients who underwent septoplasty or rhinoplasty. A chart review of patients who underwent either septoplasty or rhinoplasty by 3 surgeons between July 2016 and June 2017 was performed, and pertinent clinical data were collected including the amount of narcotic pain medications prescribed. A telephone interview was then conducted to assess opioid usage and pain control regimen postoperatively. The number of opioid tablets prescribed and the number consumed were converted to total morphine milligram equivalent (MME) for uniform comparison. A total of 75 patients met the inclusion criteria, and 64 completed the telephone survey. Among these 64 patients, the mean (standard deviation [SD]) prescribed MME was 289.7 (101.3), and the mean (SD) consumed MME was 100.6 (109). Similarly, the mean (SD) number of opioid tablets prescribed was 42.4 (9.7), and the mean number of tablets consumed was 14.7 (16.3). Gender, procedure performed (septoplasty or rhinoplasty), use of Doyle splints, and surgeon were not associated with the amount of opioids prescribed or used. Subjective pain control was the only factor associated with an increase in opioid use ( P = .0288). There was an overabundance of opioid pain medications prescribed compared to the amount consumed for pain control after septoplasty or rhinoplasty. Abuse of prescription opioids represents an important component of the nation's opioid crisis. Surgeons must be cognizant of the problem and adjust prescribing practices accordingly.

Objective: An increasing number of facilities offer Upper Airway Stimulation (UAS) with varying levels of experience. The goal was to quantify whether a surgical learning curve exists in operative or sleep outcomes in UAS., Methods: International multi-center retrospective review of the ADHERE registry, a prospective international multi-center study collecting UAS outcomes. ADHERE registry centers with at least 20 implants and outcomes data through at least 6-month follow-up were reviewed. Cases were divided into two groups based on implant order (the first 10 or second 10 consecutive implants at a given site). Group differences were assessed using Mann-Whitney U-tests, Chi-squared tests, or Fisher's Exact tests, as appropriate. A Mann-Kendall trend test was used to detect if there was a monotonic trend in operative time. Sleep outcome equivalence between experience groups was assessed using the two one-sided tests approach., Results: Thirteen facilities met inclusion criteria, contributing 260 patients. Complication rates did not significantly differ between groups ( P  = .808). Operative time exhibited a significant downward trend ( P  < .001), with the median operative time dropping from 150 minutes for the first 10 implants to 134 minutes for the subsequent 10 implants. The decrease in AHI from baseline to 12-month follow-up was equivalent between the first and second ten (22.8 vs 21.2 events/hour, respectively, P  < .001). Similarly, the first and second ten groups had equivalent ESS decreases at 6 months (2.0 vs 2.0, respectively, P  < .001). ESS outcomes remained equivalent for those with data through 12-months., Conclusions: Across the centers' first 20 implants, an approximately 11% reduction operative time was identified, however, no learning curve effect was seen for 6-month or 12-month AHI or ESS over the first twenty implants. Ongoing monitoring through the ADHERE registry will help measure the impact of evolving provider and patient specific characteristics as the number of implant centers increases.

Background: Ubiquitously expressed CTCF is involved in numerous cellular functions, such as organizing chromatin into TAD structures. In contrast, its paralog, CTCFL, is normally only present in the testis. However, it is also aberrantly expressed in many cancers. While it is known that shared and unique zinc finger sequences in CTCF and CTCFL enable CTCFL to bind competitively to a subset of CTCF binding sites as well as its own unique locations, the impact of CTCFL on chromosome organization and gene expression has not been comprehensively analyzed in the context of CTCF function. Using an inducible complementation system, we analyze the impact of expressing CTCFL and CTCF-CTCFL chimeric proteins in the presence or absence of endogenous CTCF to clarify the relative and combined contribution of CTCF and CTCFL to chromosome organization and transcription., Results: We demonstrate that the N terminus of CTCF interacts with cohesin which explains the requirement for convergent CTCF binding sites in loop formation. By analyzing CTCF and CTCFL binding in tandem, we identify phenotypically distinct sites with respect to motifs, targeting to promoter/intronic intergenic regions and chromatin folding. Finally, we reveal that the N, C, and zinc finger terminal domains play unique roles in targeting each paralog to distinct binding sites to regulate transcription, chromatin looping, and insulation., Conclusion: This study clarifies the unique and combined contribution of CTCF and CTCFL to chromosome organization and transcription, with direct implications for understanding how their co-expression deregulates transcription in cancer.

We have expressed a synthetic gene encoding the insecticidal neurotoxin of scorpion Androctonus australis (AaIT) in NIH/3T3 mouse fibroblast cells under the transcriptional control of a murine retroviral long terminal repeat. The secretion of the toxin into the culture medium was directed by the signal peptide of human interleukin-2. The recombinant AaIT produced was selectively toxic to yellow-fever mosquito larvae and harmless to mice.