TNF-α priming enhances CD4+FoxP3+ regulatory T-cell suppressive function in murine GVHD prevention and treatment.

CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) have been shown to effectively prevent graft-versus-host disease (GVHD) when adoptively transferred in murine models of hematopoietic cell transplantation and in phase 1/2 clinical trials. Critical limitations to Treg clinical application are the paucity of cells and limited knowledge of the mechanisms of in vivo function. We hypothesized that inflammatory conditions in GVHD modify Treg characteristics and activity. We found that peripheral blood of recipient animals during acute GVHD (aGVHD) induces Treg activation and enhances their function. The serum contains high levels of tumor necrosis factor-α (TNF-α) that selectively activates Tregs without impacting CD4(+)FoxP3(-) T cells. TNF-α priming induces Treg in vivo proliferation, whereas it limits the ability of CD4 and CD8 conventional T cells (Tcons) to proliferate and induce GVHD. TNF-α-primed Tregs prolong animal survival as compared with unprimed Tregs when used at an unfavorable Treg:Tcon ratio, demonstrating enhanced in vivo efficacy of TNF-α-primed Tregs. Because TNF-α is produced by several immune cells during inflammation, our work elucidates aspects of the physiologic mechanisms of Treg function. Furthermore, TNF-α priming of Tregs provides a new tool to optimize Treg cellular therapies for GVHD prevention and treatment.

Tracheostomy Incidence and Complications: A National Database Analysis.

OBJECTIVE: To describe the incidence of tracheostomy-related complications and identify prognostic risk factors. STUDY DESIGN: Administrative database analysis. SETTING: Outpatient and inpatient insurance claims records obtained from a national database. METHODS: PearlDiver, a private analytics database of insurance claims from Medicare, Medicaid, and commercial insurance companies, was used to identify patients who underwent tracheostomies and associated complications between January 2010 and October 2021 by CPT and ICD-9/ICD-10 codes. RESULTS: A total of 198,143 tracheostomies were identified from PearlDiver, and at least 1 tracheostomy-related complication occurred within 90 days of the procedure in 22,802 (10.3%) of these cases. The proportion of tracheostomy-related complications was 2.3 times higher in 2019 compared to 2010 (95% confidence interval [CI]: 2.18-2.52). The risk of developing tracheostomy-complications was associated with the hospital region (highest in the Midwest as compared to the West [odds ratio [OR] = 1.32; 95% CI: 1.25-1.39]), provider specialty (highest for otolaryngologists as compared to nonsurgical physicians [OR = 2.22; 95% CI: 2.10-2.34]), insurance plan type (lowest for cash payment compared to Medicaid [OR = 0.70, 95% CI: 0.50-0.94]), and Elixhauser Comorbidity Index (ECI) (highest in patients with ECI of 7+ compared to 0-1 [OR = 2.96; 95% CI: 2.17-3.24]), but was not significantly associated with patient age (OR = 0.99; 95% CI: 0.99-0.99), or gender (OR = 1.04; 95% CI: 1.01-1.07). CONCLUSIONS: Complications after tracheostomy are common and sicker patients are at higher risk for complications. Identifying factors associated with increased risk for complications could help to improve patient and family counseling, guide quality improvement initiatives, and inform future studies on tracheostomy outcomes.

Mandibular Advancement vs Combined Airway and Positional Therapy for Snoring: A Randomized Clinical Trial.

Importance: Approximately 150 million individuals in the US snore in the absence of obstructive sleep apnea (primary snoring), but few studies have examined the efficacy of treatments for snoring or evaluated the effect of snoring in sleeping partners. Objective: To evaluate the efficacy of 2 treatments for primary snoring. Design, Setting, and Participants: This pilot randomized clinical trial that included a convenience sample of people who snore without sleep apnea and their sleeping partner who underwent 4 weeks of snoring treatment was conducted at an academic medical center between October 3, 2022, and July 3, 2023. Interventions: Fifty couples were randomized to either use a mandibular advancement device (MAD) or receive combined airway and positional therapy (CAPT; external nasal dilator, nasal saline lavage with mometasone, mouth taping, and lateral positional therapy). Main Outcome and Measure: Percentage of sleeping partners who reported that their partner's snoring was either very much improved or much improved (responder) on the Clinical Global Impression of Improvement scale. Results: A total of 42 dyads completed the study; 23 (55%) were randomized to MAD and 19 (45%) to CAPT. Among people who snore, 26 (62%) were female, and the mean (SD) age was 48 (14) years. Of 23 dyads randomized to MAD, 21 people who snore (91%) were rated by the sleeping partner as a responder, while 11 of the 19 dyads (58%) randomized to CAPT were rated by the sleeping partner as responder, resulting in a difference of 33 percentage points (95% CI, 8-58) and a number needed to treat of 3. Of the 10 participants who were withdrawn, 4 were withdrawn due to adverse effects of the treatment that were evenly distributed between the MAD (n = 2) and CAPT (n = 2) groups. Conclusion and Relevance: The results of this randomized clinical trial showed that the MAD may be more effective than CAPT for treating primary snoring, while both treatment options were found to reduce primary snoring. Physicians should have a patient-centered discussion to determine which treatment is best for individual patients with primary snoring, weighing convenience, adverse effects, and cost as factors. Trial Registration: ClinicalTrials.gov Identifier: NCT05756647.

Impact of Reverse Septal Flap on Morbidity of Nasoseptal Flap Reconstruction of Skull Base Defects.

BACKGROUND: The workhorse for endonasal reconstruction of skull base defects is the posteriorly-based nasoseptal flap (NSF). Postoperative nasal deformities and decreased olfaction are potential complications of NSF. The reverse septal flap (RSF) minimizes the donor site morbidity of the NSF by covering the exposed cartilage of the anterior septum. Currently, there are minimal data examining its effect on outcomes including nasal dorsum collapse and olfaction. OBJECTIVE: Our study aims to clarify whether the RSF should be utilized when the option exists. METHODS: Adult patients undergoing endoscopic endonasal approach (EEA) surgery of the skull base (transsellar/transplanum/transclival approaches) with NSF reconstruction were identified. Data from 2 separate cohorts, one retrospective and one prospective, were collected. Follow-up was at least 6 months. Patients were photographed preoperatively and postoperatively using standard rhinoplastic nasal views. Patients completed the University of Pennsylvania Smell Identification Test (UPSIT) and the 22-item Sino-Nasal Outcome Test (SNOT-22) preoperatively and postoperatively and were also queried regarding subjective changes in nasal appearance and plans for cosmetic surgery following EEA. RESULTS: There were no statistically significant differences in the change in UPSIT and SNOT-22 scores between patients receiving RSF and other reconstructive groups (either NSF without RSF or no NSF). One of 25 patients who were reconstructed with an NSF with RSF reported a change in nasal appearance; none were considering reconstructive surgery. The proportion of patients reporting changes in appearance was significantly lower in the NSF with RSF group as compared to the NSF without RSF group (P = .012). CONCLUSION: The use of an RSF to limit donor site morbidity of the NSF was shown to significantly decrease the proportion of patients who reported nasal deformities and did not show a significant difference in patient-reported sinonasal outcomes. Given these findings, RSF should be considered whenever an NSF is used for reconstruction.

Clinical and Radiologic Characterization of Frontal Sinusitis in the Pediatric Population.

INTRODUCTION: Frontal sinusitis in the pediatric population is a disease that has not been thoroughly studied or characterized. The goals of this study are to characterize the clinical presentation, radiologic variables, treatment modalities, complications, and prognosis associated with acute and chronic frontal sinus disease in the pediatric population. METHODS: IRB-approved retrospective cohort study of pediatric patients who were diagnosed with acute (AFS) or chronic frontal sinusitis (CFS) and underwent frontal sinus surgery at a tertiary level Children's Hospital from 2006 to 2016. Patients with AFS were compared to patients with CFS. Statistical analysis completed using chi-square test or Fisher's exact test, statistical significance set at P < .05. RESULTS: A total of 19 patients with AFS and 15 patients with CFS were analyzed. There was a male predominance in AFS and female predominance in CFS (P < .05).AFS patients were less likely to have allergies, prior sinus disease, or significant comorbidities (P < .05).Additionally, AFS patients presented with constitutional, neurologic, and ocular symptoms. The CFS group had predominantly sinonasal symptoms. CT-scan analysis showed that AFS patients had higher prevalence of complex frontal anatomy (Type-II cells, concha bullosa) compared with CFS patients (P < .05). Culture results were positive in 78% of the AFS group, with S. Anginosus (53%), Anaerobes (20%), and normal flora (17%). In the CFS group cultures were positive in 60% of the patients, 56% grew normal flora, 13% H. Influenzae, 6.5% Pseudomonas, and 24.5% other species. CFS patients were more likely to have persistent sinus disease and require repeat sinus procedures (P < .05). CONCLUSION: There are 2 distinct presentations of frontal sinus disease in the pediatric population. Patients with AFS vary significantly from those with CFS. Males, ages 13 to 18 years old, who cultured positive for S. Anginosus (former S.Milleri) dominated the AFS subgroup. Whereas as female patients with a history of allergic rhinitis and muco-cilliary disease were more prominent in the CRS subgroup. Correct identification and understanding of these 2 different entities are crucial for the appropriate short and long-term patient management.

Two for the price of one: Prevalence, demographics and treatment implications of multiple HPV mediated Head and Neck Cancers.

OBJECTIVES: HPV mediated head and neck squamous cell carcinoma (HPVmHNSCC) is increasing in prevalence in the United States, as are reports of patients with multiple HPVmHNSCCs. The prevalence, demographics, and treatment implications of this emerging clinical entity are poorly understood. MATERIALS AND METHODS: We performed a multitiered assessment of patients with multiple HPVmHNSCC including: 1. systematic review of the literature, 2. query of the 2017 Surveillance, Epidemiology and End Results (SEER) database and 3. institutional level reporting at two high volume academic centers. RESULTS: Systematic literature review: 13 articles met inclusion criteria (48 patients with multiple HPVmHNSCC). Pooled prevalence rate of multiple HPVmHNSCC was 2.64%. SEER database: 60(0.95%) patients with HPVmHNSCC had two tumors. Patients with multiple HPVmHNSCC were more likely to be younger and present with a lower T and N stage (p < 0.025 for all). The second identified tumor was more likely to be contralateral, found synchronously, of smaller size, and to occur in the tonsil (p < 0.05 for all). Institutional reporting: 17(1.69%) patients with HPVmHNSCC had two primary tumors. Similar to the SEER database, patients with multiple HPVmHNSCC were more likely to present with a low T stage and tonsil location (p < 0.007 for both). CONCLUSION: Multiple HPVmHNSCCs occur in a subset of HPVmHNSCC cases with distinct characteristics. Thorough interrogation of all oropharyngeal subsites should be performed as part of the initial workup for HPVmHNSCC, with consideration given to contralateral tonsillectomy at the time of surgical resection for HPV mediated tonsil cancers due to the prevalence of contralateral tonsil primaries.

Foxp3+ regulatory T cells maintain the bone marrow microenvironment for B cell lymphopoiesis.

Foxp3+ regulatory T cells (Treg cells) modulate the immune system and maintain self-tolerance, but whether they affect haematopoiesis or haematopoietic stem cell (HSC)-mediated reconstitution after transplantation is unclear. Here we show that B-cell lymphopoiesis is impaired in Treg-depleted mice, yet this reduced B-cell lymphopoiesis is rescued by adoptive transfer of affected HSCs or bone marrow cells into Treg-competent recipients. B-cell reconstitution is abrogated in both syngeneic and allogeneic transplantation using Treg-depleted mice as recipients. Treg cells can control physiological IL-7 production that is indispensable for normal B-cell lymphopoiesis and is mainly sustained by a subpopulation of ICAM1+ perivascular stromal cells. Our study demonstrates that Treg cells are important for B-cell differentiation from HSCs by maintaining immunological homoeostasis in the bone marrow microenvironment, both in physiological conditions and after bone marrow transplantation.

T cells expressing chimeric antigen receptor promote immune tolerance.

Cellular therapies based on permanent genetic modification of conventional T cells have emerged as a promising strategy for cancer. However, it remains unknown if modification of T cell subsets, such as Tregs, could be useful in other settings, such as allograft transplantation. Here, we use a modular system based on a chimeric antigen receptor (CAR) that binds covalently modified mAbs to control Treg activation in vivo. Transient expression of this mAb-directed CAR (mAbCAR) in Tregs permitted Treg targeting to specific tissue sites and mitigated allograft responses, such as graft-versus-host disease. mAbCAR Tregs targeted to MHC class I proteins on allografts prolonged islet allograft survival and also prolonged the survival of secondary skin grafts specifically matched to the original islet allograft. Thus, transient genetic modification to produce mAbCAR T cells led to durable immune modulation, suggesting therapeutic targeting strategies for controlling alloreactivity in settings such as organ or tissue transplantation.