American Rhinologic Society Expert Practice Statement: Indications and Recommendations for Septoplasty in Children.

The goal of this American Rhinologic Society Expert Practice Statement (EPS) is to provide recommendations and guidance through evidence-based consensus statements regarding pediatric septoplasty. This EPS was developed following the previously published methodology and approval process. The topics of interest included appropriate indications, safety and efficacy, timing, relevant quality of life instruments, and surgical techniques. Following a modified Delphi approach, six statements were developed, five of which reached consensus and one that did not. These statements and accompanying evidence are summarized along with an assessment of future needs.

Impact of allergic rhinitis on quality of life in patients with chronic rhinosinusitis.

OBJECTIVES: To evaluate the impact of allergic rhinitis (AR) on the quality of life (QoL) in patients with chronic rhinosinusitis (CRS). METHODS: Retrospective cross-sectional study of adult patients with CRS presenting to our clinic between August 2020 and February 2023 was performed. AR was diagnosed based on a positive skin or blood allergy test. Patients' characteristics, AR status, comorbidities, endoscopy scores, and SNOT-22 scores were collected. RESULTS: A total of 514 CRS patients were included, with 265 (51.6 %) patients with AR. CRS patients with AR were younger (p = 0.004), more likely to be female (p < 0.001), and more likely to have asthma (p < 0.001). Polyp status and endoscopy scores did not differ between patients with and without AR. Baseline SNOT-22 scores were slightly worse in the AR cohort (43.6 vs 38.7, p = 0.007), which was mainly secondary to rhinologic (p = 0.002), extrarhinologic (p = 0.007), and ear/facial (p = 0.007) subdomains. Worse rhinologic and extrarhinologic scores were associated with the presence of AR after adjusting for confounding variables (Coef = 1.55, p = 0.011; and Coef = 0.83, p = 0.021 respectively). CONCLUSION: The impact of allergic rhinitis on QoL is mainly on the nasal symptoms. Further studies should look at the role of AR on the QoL of different CRS endotypes; and at the role of AR-specific treatment, such as immunotherapy, on the QoL of patients with CRS.

Correlation of patient reported outcome measures with endoscopic findings in pediatric chronic adenoiditis and chronic rhinosinusitis.

BACKGROUND: Studies in adult chronic rhinosinusitis (CRS) showed poor correlation between patient reported outcome measures (PROMs) and objective findings. Our goal is to study the correlation between the sinus and nasal quality of life (SN-5) and the 22-items sinonasal outcome test (SNOT-22) surveys with endoscopy findings in children with chronic adenoiditis (CA) and CRS. METHODS: Cross-sectional study of all pediatric patients (age 2-18) presenting for CA or CRS was performed. Patients and caregivers were asked to fill the SN-5 and SNOT-22 questionnaires at initial and follow up visits. Demographics and comorbidities were collected. Objective findings included endoscopy Modified Lund-Kennedy (MLK) scores and adenoid tissue size. RESULTS: 124 children were included, with mean age of 9.9 years (SD = 4.8) and 46.8% female. 36.3% had allergic rhinitis, 23.4% had asthma, and 4% had obstructive sleep apnea. Moderate correlation was found between the rhinologic domain of SNOT-22 and MLK scores (r = 0.36, p = 0.001) and between SN5 scores and adenoid size in all patients (r = 0.39, p < 0.001). SNOT-22 scores showed moderate correlation with adenoid size (r = 0.42, p < 0.001) more specifically in CA patients (r = 0.54, p < 0.001). The correlation of SN5 and MLK scores were higher in children with allergic rhinitis or asthma. The correlation between SN5 and adenoid size was lower in children with allergic rhinitis or asthma. CONCLUSION: There is discrepancy between the subjective measures and the objective findings in children with CA or CRS. The physical exam findings may not reflect the effect of CRS on the quality of life of children.

Performance status at the time of lung retransplant predicts long-term function.

BACKGROUND: Lung retransplantation is offered to select patients with chronic allograft dysfunction. Given the increased risk of morbidity and mortality conferred by retransplantation, post-transplant function should be considered in the decision of who and when to list. The aim of this study is to identify predictors of post-operative disability in patients undergoing lung retransplantation. METHODS: Data were collected from the UNOS national dataset and included all patients who underwent lung retransplant from May 2005-March 2023. Pre- and post-operative function was reported by the Karnofsky Performance Status (KPS) and patients were stratified based on their needs. Cumulative link mixed effects models identified associations between pre-transplant variables and post-transplant function. RESULTS: A total of 1275 lung retransplant patients were included. After adjusting for between-group differences, pre-operative functional status was predictive of post-transplant function; patients requiring Total Assistance ( n = 740) were 74% more likely than No/Some Assistance patients (n = 535) to require more assistance in follow-up (OR 1.74, 95% CI 1.13-2.68, p = .012). Estimated one year survival of Total Assistance patients is lower than No/Some Assistance Recipients (72% vs. 82%, CI 69%-75%; 79%-86%) but similar to overall re-transplant survival (76%, CI 74%-79%). CONCLUSION: Both survival and regain of function in patients requiring Total Assistance prior to retransplant may be higher than previously reported. Pre-operative functional status is predictive of post-operative function and should weigh in the selection, timing and post-operative care of patients considered for lung retransplantation.

Role of Sinonasal Anatomic Variants in Recurrent Acute Rhinosinusitis.

OBJECTIVES: Prior studies evaluating the role of sinonasal anatomic variants with recurrent acute rhinosinusitis (RARS) are limited by inconsistent results. The goal of this study is to evaluate the association between sinonasal anatomic variants and RARS. METHODS: A 1:2 retrospective case-control study was conducted using patients presenting to the rhinology clinic from August 2020 to January 2023. A total of 60 patients with RARS were compared to 120 control patients. RARS was diagnosed based on the International Consensus Statement on Allergy and Rhinology criteria of four or more independent episodes of acute rhinosinusitis per year with at least one episode documented by objective findings, with complete resolution of the infection in-between episodes. Sinonasal anatomic variants included nasal septal deviation (NSD), concha bullosa (CB), infraorbital (Haller) cells, nasal septal spur in the middle meatus, and frontal sinus cells (supra-agger, supra-agger frontal, and suprabullar frontal cells). RESULTS: Age was similar in RARS and control patients (47.4 ± 16.5 vs. 49.3 ± 14.5, p = 0.432). Both the RARS group and control group were more likely to be female (78.3% vs. 77.5%, p = 0.899). There was no significant association between NSD and RARS compared to the control group (OR = 0.97, p = 0.916), and no significant association between any of the anatomic variants and RARS [infraorbital cells (OR = 0.64, p = 0.167), CB (OR = 0.84, p = 0.596), spur in the middle meatus (OR = 1.28, p = 0.514), supra-agger (OR = 0.88, p = 0.708), supra-agger frontal cells (OR = 0.97, p = 0.939), or suprabullar frontal cells (OR = 1.13, p = 0.766)]. CONCLUSION: Our findings suggest no association between nasal septal deviation or any of the anatomic variants studied and RARS. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:3489-3492, 2024.

Dissection of a CTCF topological boundary uncovers principles of enhancer-oncogene regulation.

Enhancer-gene communication is dependent on topologically associating domains (TADs) and boundaries enforced by the CCCTC-binding factor (CTCF) insulator, but the underlying structures and mechanisms remain controversial. Here, we investigate a boundary that typically insulates fibroblast growth factor (FGF) oncogenes but is disrupted by DNA hypermethylation in gastrointestinal stromal tumors (GISTs). The boundary contains an array of CTCF sites that enforce adjacent TADs, one containing FGF genes and the other containing ANO1 and its putative enhancers, which are specifically active in GIST and its likely cell of origin. We show that coordinate disruption of four CTCF motifs in the boundary fuses the adjacent TADs, allows the ANO1 enhancer to contact FGF3, and causes its robust induction. High-resolution micro-C maps reveal specific contact between transcription initiation sites in the ANO1 enhancer and FGF3 promoter that quantitatively scales with FGF3 induction such that modest changes in contact frequency result in strong changes in expression, consistent with a causal relationship.

Gender Differences in Adults With Chronic Rhinosinusitis: A Scoping Review.

OBJECTIVE: Gender differences in chronic rhinosinusitis (CRS) have been demonstrated in many studies over the last 15 years. The purpose of this scoping review is to investigate the current knowledge on gender differences in CRS and to analyze the gaps in the literature. DATA SOURCES: A systematic search of PubMed, Cochrane Library, and Embase databases was performed. REVIEW METHODS: This scoping review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. Studies that evaluated gender differences in CRS were included in the review. RESULTS: Of the 523 abstracts reviewed, a total of 23 studies met the criteria for inclusion. Articles consisted of retrospective and prospective cohort studies. They were divided into 3 categories based on whether they evaluated gender differences in (1) presentation and baseline quality of life, (2) pathophysiology, and/or (3) outcomes of treatment. Eleven studies addressed differences in presentation, 5 addressed differences in pathophysiology, and 10 dealt with differences in outcomes after surgical or medical management. Most of the studies showed worse baseline QoL secondary to CRS in women, with outcome of treatment being similar in both genders. CONCLUSION: The experience of CRS appears to vary between genders, with women experiencing a greater subjective burden of disease than men, though with similar outcomes after treatment. Further research is indicated, particularly involving the pathophysiology of CRS, to fully understand the underlying causes of these discrepancies.

Lung transplantation in HIV seropositive recipients: An analysis of the UNOS registry.

BACKGROUND: Experience with lung transplantation (LT) in patients with human immunodeficiency virus (HIV) is limited. Many studies have demonstrated the success of kidney and liver transplantation in HIV-seropositive (HIV+) patients. Our objective was to conduct a national registry analysis comparing LT outcomes in HIV+ to HIV-seronegative (HIV-) recipients. METHODS: The United Network for Organ Sharing database was queried to identify LTs performed in adult HIV+ patients between 2016 and 2023. Patients with unknown HIV status, multiorgan transplants, and redo transplants were excluded. The primary endpoints were mortality and graft rejection. Survival time was analyzed using Kaplan-Meier analysis. RESULTS: The study included 17 487 patients, 67 of whom were HIV+. HIV+ recipients were younger (59 vs. 62 years, p = .02), had higher pulmonary arterial pressure (28 vs. 25 mm Hg, p = .04), and higher lung allocation scores (47 vs. 41, p = .01) relative to HIV- recipients. There were no differences in graft/recipient survival time between groups. HIV+ recipients had higher rates of post-transplant dialysis (18% vs. 8.4%, p = .01), but otherwise had similar post-transplant outcomes to HIV-recipients. CONCLUSIONS: This national registry analysis suggests LT outcomes in HIV+ patients are not inferior to outcomes in HIV- patients and that well-selected HIV+ recipients can achieve comparable patient and graft survival rates relative to HIV- recipients.

Impact of recurrent acute rhinosinusitis on quality of life.

KEY POINTS: Quality of life (QoL) in patients with recurrent acute rhinosinusitis (RARS) is understudied. QoL for RARS patients is similar to chronic rhinosinusitis patients, although objective disease severity is lower. QoL of RARS patients is similarly affected during active and inactive infection.

Gender Differences in Quality of Life of Adolescent Patients With Chronic Rhinosinusitis.

OBJECTIVES: To identify the differences in the impact of chronic rhinosinusitis (CRS) between female and male adolescent patients at presentation. STUDY DESIGN: Cross sectional study. METHODS: Adolescent patients, age 12 to 18 years old, presenting to our Otolaryngology clinic between August 2020 and April 2023 for CRS were asked to fill both the SNOT-22 and the SN5 forms. Female and male cohorts were compared regarding their demographics, comorbidities, subjective and objective disease measurements, and choice of treatment. RESULTS: Sixty-six patients were included, 30 female and 36 male patients. There were no differences in age, allergic rhinitis, asthma, obstructive sleep apnea, presence of nasal septal deviation, and objective disease severity (P > .05 for all). At presentation, mean overall SNOT-22, ear/facial, sleep, and psychological domains were all higher in female patients (43vs 30.9, P = .02; 9.1vs 6, P = .03; 11.8vs 8.3, P = .07; 14.1vs 8.8, P = .02 respectively). SN5 scores and overall QoL visual analog scale were similar in females and males. CONCLUSION: Female patients with CRS show higher subjective disease burden. Incorporating data on gender-specific differences may be important to personalize treatment decision making.

Associations between the stanford integrated psychosocial assessment for transplant and one-year lung transplant medical and psychosocial outcomes.

The Stanford Integrated Psychosocial Assessment for Transplant (SIPAT) is a standardized measure of the psychosocial risk profile of solid organ transplant candidates. While studies have found associations between this measure and transplant outcomes, to date this has not been examined in lung transplant recipients. We examined relations between pre-transplant SIPAT scores and 1-year lung transplant medical and psychosocial outcomes in a sample of 45 lung transplant recipients. The SIPAT was significantly associated with 6-minute walk test (χ2(1) = 6.47, p = .010), number of readmissions (χ2(1) = 6.47, p = .011), and mental health services utilization (χ2(1) = 18.15, p < .001). It was not a significantly associated with the presence of organ rejection or mortality (ps > 0.10). Results suggest that the SIPAT can help identify patients who are at an elevated risk for transplant complications and thus would benefit from services to mitigate risk factors and improve outcomes.

Risk Factors associated with Recurrent Acute Rhinosinusitis.

KEY POINTS: Few studies have evaluated the association of recurrent acute rhinosinusitis (RARS) with other comorbidities. Allergic rhinitis, asthma, primary antibody deficiency, and autoimmune disorders are associated with RARS. Evaluation for these comorbidities should be considered when treating patients with RARS.

Role of Acute Rhinosinusitis in Periorbital Infections in Children.

OBJECTIVE: Periorbital cellulitis in children are commonly caused by acute rhinosinusitis (ARS). This study investigated the association of ARS and the severity of periorbital cellulitis in children. STUDY DESIGN: Retrospective case-control study of children with periorbital cellulitis with ARS versus periorbital cellulitis without ARS. SETTING: Patients were seen at West Virginia University Children's Hospitals between August 2011 to August 2022. METHODS: Patients were divided into cases and controls based on presence or absence of ARS. ARS was defined based on clinical symptoms with objective presence of disease on CT scan. Patients' characteristics, treatment, hospital length of stay, and readmission were collected. RESULTS: The sample consisted of 118 pediatric patients with orbital cellulitis. Patients with ARS were younger than patients without ARS (6.3 vs 8.5, p = 0.025), however there were no sex differences between two groups (p = 0.540). The ARS group had higher incidence of postseptal cellulitis (51.5% vs 9.6%, p < 0.001). As compared to patients without ARS, patients with ARS were more likely to be admitted (p < 0.001), have a longer length of stay (median of 3.5 days vs 0.5 days, p < 0.001), require IV antibiotics (95.3% vs 54.9%, p < 0.001), and require surgical intervention (23.1% vs 5.8%, p < 0.001). Readmission rate was similar between the two groups. CONCLUSION: Children presenting with acute periorbital cellulitis who have ARS tend to have more severe infection requiring higher level of care. ARS should be assessed and incorporated into the plan of care of pediatric patients with periorbital infections.

Association of autoimmune disorders with chronic rhinosinusitis in adults.

INTRODUCTION: Increasing evidence suggests that autoimmune disorders and their immunomodulating medications may increase the risk of rhinosinusitis compared to rhinitis. GOAL: To investigate the association between autoimmune disorders and rhinosinusitis. METHODS: We performed a case-control study of patients referred to West Virginia University from August 2020 to October 2022 for rhinologic complaints. Rhinosinusitis patients were diagnosed with either chronic rhinosinusitis (CRS) or recurrent acute rhinosinusitis (RARS). These patients were compared to non-rhinosinusitis patients. Patients' characteristics, comorbidities, and type of treatment of autoimmune disorders were reviewed. RESULTS: The sample consisted of 527 rhinosinusitis [184 CRS without nasal polyps (CRSsNP), 263 CRS with nasal polyps (CRSwNP) and 80 RARS patients] patients and 564 non-rhinosinusitis patients. Patients with rhinosinusitis were more likely to be older, males, have asthma, and have current and past smoking history (all with p-value < 0.05). Autoimmune disorders, primary antibody deficiency, and immunomodulator agents were more common in rhinosinusitis patients (16.5 % vs 9.4 %, OR = 1.9, p < 0.001; 5.1 % vs 0.5 %, OR = 10.1, p < 0.001; and 3.8 % vs 1.1 %, OR = 3.7, p = 0.003 respectively). Multivariate logistic regression adjusting for confounders showed that autoimmune disorders were strongly associated with rhinosinusitis [OR = 1.6, 95 % CI = 1.10-2.48], whereas the immunomodulators did not reach statistical significance [OR = 2.4, 95 % CI = 0.87-6.47]. Subgroup analysis showed the autoimmune disorders did not significantly differ between CRS and RARS groups [OR = 1.0, 95 % CI = 0.5-2.1], or between the CRSsNP and CRSwNP groups [OR = 0.9, 95 % CI = 0.5-1.7]. CONCLUSION: Autoimmune disorders are associated with rhinosinusitis, both CRS and RARS, independently of other risk factors.

Programs, Origins, and Niches of Immunomodulatory Myeloid Cells in Gliomas.

Gliomas are incurable malignancies notable for an immunosuppressive microenvironment with abundant myeloid cells whose immunomodulatory properties remain poorly defined. Here, utilizing scRNA-seq data for 183,062 myeloid cells from 85 human tumors, we discover that nearly all glioma-associated myeloid cells express at least one of four immunomodulatory activity programs: Scavenger Immunosuppressive, C1Q Immunosuppressive, CXCR4 Inflammatory, and IL1B Inflammatory. All four programs are present in IDH1 mutant and wild-type gliomas and are expressed in macrophages, monocytes, and microglia whether of blood or resident myeloid cell origins. Integrating our scRNA-seq data with mitochondrial DNA-based lineage tracing, spatial transcriptomics, and organoid explant systems that model peripheral monocyte infiltration, we show that these programs are driven by microenvironmental cues and therapies rather than myeloid cell type, origin, or mutation status. The C1Q Immunosuppressive program is driven by routinely administered dexamethasone. The Scavenger Immunosuppressive program includes ligands with established roles in T-cell suppression, is induced in hypoxic regions, and is associated with immunotherapy resistance. Both immunosuppressive programs are less prevalent in lower-grade gliomas, which are instead enriched for the CXCR4 Inflammatory program. Our study provides a framework to understand immunomodulatory myeloid cells in glioma, and a foundation to develop more effective immunotherapies.

Lung Transplantation Outcomes in Recipients Aged 70 Years or Older and the Impact of Center Volume.

OBJECTIVE: To evaluate trends and outcomes of lung transplants (LTx) in recipients ≥ 70 years. METHODS: We performed a retrospective analysis of the UNOS database identifying all patients undergoing LTx (May 2005-December 2022). Baseline characteristics and postoperative outcomes were compared by age (<70 years, ≥70 years) and center volume. Kaplan-Meier analyses were performed with pairwise comparisons between subgroups. RESULTS: 34,957 patients underwent LTx, of which 3236 (9.3%) were ≥70 years. The rate of LTx in recipients ≥ 70 has increased over time, particularly in low-volume centers (LVCs); consequently, high-volume centers (HVCs) and LVCs perform similar rates of LTx for recipients ≥ 70. Recipients ≥ 70 had higher rates of receiving from donor after circulatory death lungs and of extended donor criteria. Recipients ≥ 70 were more likely to die of cardiovascular diseases or malignancy, while recipients < 70 of chronic primary graft failure. Survival time was shorter for recipients ≥ 70 compared to recipients < 70 old (hazard ratio (HR): 1.36, 95% confidence interval (CI): 1.28-1.44, p < 0.001). HVCs were associated with a survival advantage in recipients < 70 (HR: 0.91, 95% CI: 0.88-0.94, p < 0.001); however, in recipients ≥ 70, survival was similar between HVCs and LVCs (HR: 1.11, 95% CI: 0.99-1.25, p < 0.08). HVCs were more likely to perform a bilateral LTx (BLT) for obstructive lung diseases compared to LVCs, but there was no difference in BLT and single LTx likelihood for restrictive lung diseases. CONCLUSIONS: Careful consideration is needed for recipient ≥ 70 selection, donor assessment, and post-transplant care to improve outcomes. Further research should explore strategies that advance perioperative care in centers with low long-term survival for recipients ≥ 70.

Examining Whether Genetic Variants Moderate the Skeletal Effects of Selective Serotonin Reuptake Inhibitors in Older Adolescents and Young Adults.

Objective: To examine whether serotonin (5-HT) related genetic variants moderate the effects of selective serotonin reuptake inhibitors (SSRIs) on skeletal outcomes. Methods: Trabecular bone mineral density (BMD) at the radius, lumbar spine (LS) BMD, total body less head (TBLH) bone mineral content (BMC) and markers of bone metabolism (osteocalcin, C-terminal telopeptide of type I collagen [CTX-1], and bone specific alkaline phosphatase to CTX-1 ratio) were examined in an observational study, enrolling 15- to 20-year-old participants, unmedicated or within a month of SSRI initiation. Variants in HTR1A (rs6295), HTR1B (rs6296), HTR1D (rs6300), HTR2A (rs6311 and rs6314), HTR2B (rs6736017), and the serotonin transporter intron 2 variable number tandem repeat (STin2 VNTR) were genotyped. Linear mixed-effects regression analysis examined associations between SSRI use, genetic variants, and skeletal outcomes. Results: After adjusting for relevant covariates, rs6295 CC and GC genotypes in 262 participants (60% female, mean ± SD age = 18.9 ± 1.6 years) were significantly associated with higher LS BMD compared to the GG genotype. Rs6311 GG SSRI users had greater LS BMD compared to nonusers (ß = 0.18, p = <0.0001). Female SSRI users with the combination of rs6295 CC+GC and rs6311 GG genotypes had greater LS BMD than female SSRI nonusers (ß = 0.29, p < 0.0001). SSRI users with the rs6295 GG genotype had higher trabecular BMD compared to nonusers (ß = 3.60, p = 0.05). No significant interactions were found for TBLH BMC or bone turnover markers. After correcting for multiple comparisons, none of the results retained significance. Conclusions: In older adolescents and young adults, HTR1A (rs6295) and HTR2A (rs6311) variants may moderate the effect of SSRIs on BMD. Sex differences may exist and require further examination. Further research with larger sample sizes is needed to confirm our preliminary findings. Clinical Trial Registration: clinicaltrials.gov NCT02147184.

Impact of supraphysiologic MDM2 expression on chromatin networks and therapeutic responses in sarcoma.

Amplification of MDM2 on supernumerary chromosomes is a common mechanism of P53 inactivation across tumors. Here, we investigated the impact of MDM2 overexpression on chromatin, gene expression, and cellular phenotypes in liposarcoma. Three independent regulatory circuits predominate in aggressive, dedifferentiated tumors. RUNX and AP-1 family transcription factors bind mesenchymal gene enhancers. P53 and MDM2 co-occupy enhancers and promoters associated with P53 signaling. When highly expressed, MDM2 also binds thousands of P53-independent growth and stress response genes, whose promoters engage in multi-way topological interactions. Overexpressed MDM2 concentrates within nuclear foci that co-localize with PML and YY1 and could also contribute to P53-independent phenotypes associated with supraphysiologic MDM2. Importantly, we observe striking cell-to-cell variability in MDM2 copy number and expression in tumors and models. Whereas liposarcoma cells are generally sensitive to MDM2 inhibitors and their combination with pro-apoptotic drugs, MDM2-high cells tolerate them and may underlie the poor clinical efficacy of these agents.