Single cell RNA sequencing of human eosinophils from nasal polyps reveals eosinophil heterogeneity in chronic rhinosinusitis tissue.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by type 2 inflammation in the United States, but the actual roles that eosinophils play in CRSwNP remain largely unclear. OBJECTIVE: To reveal the roles and heterogeneity of eosinophils in nasal polyp (NP) tissue, we performed single cell RNA sequencing (scRNA-Seq) analysis of NP tissue. METHODS: Sinonasal tissues (NP and control sinus tissue) and patient matched peripheral blood (PB) samples were obtained from 5 control patients and 5 patients with CRSwNP. Eosinophils were enriched before processing for scRNA-Seq. The gene expression profiles in eosinophils were determined by microwell-based scRNA-Seq technology (BD Rhapsody platform). We predicted the overall function of NP eosinophils by Gene Ontology (geneontology.org) enrichment and pathway analyses and confirmed expression of selected genes by flow cytometry. RESULTS: After filtering out contaminating cells, we detected 5,542 eosinophils from control PB, 3,883 eosinophils from CRSwNP PB, 101 eosinophils from control sinus tissues (not included in further analyses), and 9,727 eosinophils from NPs by scRNA-Seq. We found that 204 genes were downregulated and 354 genes upregulated in NP eosinophils compared to all PB eosinophils (>1.5-fold, Padj < .05). Upregulated genes in NP eosinophils were associated with activation, cytokine-mediated signaling, growth factor activity, NF-κB signaling, and antiapoptotic molecules. NP eosinophils displayed 4 clusters revealing potential heterogeneity of eosinophils in NP tissue. CONCLUSIONS: Elevated eosinophils in NP tissue appear to exist in several subtypes that may play important pathogenic roles in CRSwNP, in part by controlling inflammation and hyperproliferation of other cells.

A pilot trial examining the effects of veteran voices and visions, an adaptation of hearing voices groups for a large public health system in the United States.

BACKGROUND: The Hearing Voices Approach, a community-based peer-led support group model, is generating interest as a novel way to engage with psychosis. Hearing Voices (HV) groups are run by peers, 'experts-by-experience', and emphasize group ownership and community-building rather than adherence to a therapist-led, predetermined structure. Diverse beliefs about experiences are respected and viewed as potentially meaningful. Groups work within each individual's explanatory framework to reframe understandings. AIMS: This paper describes the effects of participation in Veteran Voices and Visions (VVV) groups, an adaptation of the HV approach, co-led by clinicians and Veteran peer support specialists, adapted for Veterans who have experienced psychosis and receive care at the VA, a large public health system in the United States. METHOD: This mixed methods pilot study has a convergent parallel design, integrating quantitative and qualitative data from participants in pre-intervention and post-intervention assessments. RESULTS: Over 16 weeks, quantitative analysis showed a statistically significant reduction in distress, due to auditory hallucinations, as measured by the Psychotic Symptom Rating Scales (PSYRATS). The Beliefs about Voices Questionnaire- Revised (BAVQ-R) results showed a reduction in malevolence and omnipotence and an increase in benevolence related to auditory hallucinations, but no change in resistance. Engagement showed a trend-level reduction. Qualitative data from midpoint (Week 8) and endpoint (Week 16) interviews revealed several perceived benefits from groups: 1) normalization and camaraderie, 2) increased hope and confidence, 3) self-understanding and reframing of experiences, and 4) building relationships outside of groups. Overall, VVV groups reduced distress due to voices, negative beliefs about voices, and perceived power of voices. CONCLUSIONS: Study findings contribute to a growing body of literature indicating HV groups support those who have experienced psychosis by reducing social isolation and fostering community, which may facilitate social integration. Overall, our findings highlight the potential benefits of adapting HV groups to health systems.

IL-13 and IL-13-induced periostin levels are specifically decreased in patients following endoscopic sinus surgery for chronic rhinosinusitis.

BACKGROUND: Type 2 (T2) inflammation plays a pathogenic role in chronic rhinosinusitis (CRS). The effects of endoscopic sinus surgery (ESS) on T2 inflammation are unknown. OBJECTIVE: The aim of this study was to compare T2 inflammatory biomarkers from middle meatal (MM) mucus for distinguishing patients with CRS from CRS-free patients, identifying major phenotypes (CRS without nasal polyps [CRSsNP] and CRS with nasal polyps [CRSwNP]), assessing endotypic change, and establishing cross-sectional and longitudinal outcomes in patients undergoing ESS. METHODS: MM mucus samples were collected from patients with CRSsNP and patients with CRSwNP before and 6 to 12 months after ESS and compared with samples from CRS-free control patients. T2 biomarkers were evaluated both continuously and using threshold-based definitions of T2 endotype to identify relationships with patient-reported (based on the 22-Item Sinonasal Outcomes Test and Chronic Rhinosinusitis Patient-Reported Outcomes Measure) and clinician-reported (radiographic and endoscopic) severity. Linear mixed models were developed to analyze clinical variables associated with T2 biomarker levels. RESULTS: A total of 154 patients with CRS (89 with CRSsNP and 65 with CRSwNP) were enrolled, with a mean interval of 9 months between ESS and follow-up. An analysis of pre-ESS MM mucus samples revealed elevated levels of T2 mediators in patients with CRSwNP versus in patients with CRSsNP and CRS-free controls. Temporally stable correlations between levels of IL-13 and IL-5, levels of periostin and complement 5a, and levels of eosinophil cationic protein (ECP) and eotaxin-3 were observed. On this basis and on the basis of pathologic significance, levels of IL-13, periostin and ECP were further analyzed. After ESS, levels of IL-13 and periostin decreased significantly, whereas ECP levels remained unchanged. Across pre- and post-ESS evaluation, the T2 endotype was associated with radiographic severity but did not predict outcomes. CRSwNP status and African American race were associated with higher levels of IL-13 and periostin, whereas ECP level was higher in patients undergoing extensive surgery. CONCLUSION: ESS decreased levels of IL-13 and periostin in the middle meatus. T2 inflammation after ESS was correlated with patient- and clinician-reported severity across phenotypes. Pre-ESS T2 inflammation did not predict post-ESS outcomes.

Effort-based decision-making as a determinant of supported employment outcomes in psychotic disorders.

Schizophrenia is associated with a heavy economic burden in the United States that is partly due to the high rates of chronic unemployment. Individual Placement and Support (IPS) is an evidenced-based type of supported employment that can improve job obtainment and work outcomes in psychotic disorders. Outcomes vary widely and a persistent challenge for IPS is low levels of engagement in the initial job search phase. Past studies have focused on interview-based motivation deficits as a key determinant of poor treatment engagement and work outcomes in schizophrenia. New validated performance-based measures of motivation, including effort-based decision-making (EBDM) tasks, may explain supported employment outcomes and provide insights into individual differences in IPS outcomes. This study investigated the degree to which IPS engagement (i.e., number of sessions attended during the first four months of service delivery) was related to baseline interview-based motivation deficits and performance on three EBDM tasks - two tasks of physical effort and one of cognitive effort (i.e., Balloon Task, Effort Expenditure for Rewards Task, Deck Choice Effort Task) - in a sample (N = 47) of people with a psychotic disorder. Results indicated that the level of EBDM performance, specifically on the Balloon Task, predicted IPS engagement, accounting for an additional 17 % of the variance above and beyond interview-based motivation deficits (total R2 = 24 %). Overall, these findings suggest that addressing motivational deficits in effort-based decision-making may be beneficial to IPS engagement, which in turn may improve the trajectory of work outcomes.

Epigenetic responses to rhinovirus exposure in airway epithelial cells are correlated with key transcriptional pathways in chronic rhinosinusitis.

BACKGROUND: Viruses may drive immune mechanisms responsible for chronic rhinosinusitis with nasal polyposis (CRSwNP), but little is known about the underlying molecular mechanisms. OBJECTIVES: To identify epigenetic and transcriptional responses to a common upper respiratory pathogen, rhinovirus (RV), that are specific to patients with CRSwNP using a primary sinonasal epithelial cell culture model. METHODS: Airway epithelial cells were collected at surgery from patients with CRSwNP (cases) and from controls without sinus disease, cultured, and then exposed to RV or vehicle for 48 h. Differential gene expression and DNA methylation (DNAm) between cases and controls in response to RV were determined using linear mixed models. Weighted gene co-expression analysis (WGCNA) was used to identify (a) co-regulated gene expression and DNAm signatures, and (b) genes, pathways, and regulatory mechanisms specific to CRSwNP. RESULTS: We identified 5585 differential transcriptional and 261 DNAm responses (FDR <0.10) to RV between CRSwNP cases and controls. These differential responses formed three co-expression/co-methylation modules that were related to CRSwNP and three that were related to RV (Bonferroni corrected p < .01). Most (95%) of the differentially methylated CpGs (DMCs) were in modules related to CRSwNP, whereas the differentially expressed genes (DEGs) were more equally distributed between the CRSwNP- and RV-related modules. Genes in the CRSwNP-related modules were enriched in known CRS and/or viral response immune pathways. CONCLUSION: RV activates specific epigenetic programs and correlated transcriptional networks in the sinonasal epithelium of individuals with CRSwNP. These novel observations suggest epigenetic signatures specific to patients with CRSwNP modulate response to viral pathogens at the mucosal environmental interface. Determining how viral response pathways are involved in epithelial inflammation in CRSwNP could lead to therapeutic targets for this burdensome airway disorder.

Sinus inflammation and chronic rhinosinusitis are associated with a diagnosis of new onset asthma in the following year.

BACKGROUND: Chronic rhinosinusitis (CRS) and asthma commonly co-occur. No studies have leveraged large samples needed to formally address whether preexisting CRS is associated with new onset asthma over time. METHODS: We evaluated whether prevalent CRS [identified in two ways: validated text algorithm applied to sinus computerized tomography (CT) scan or two diagnoses] was associated with new onset adult asthma in the following year. We used electronic health record data from Geisinger from 2008 to 2019. For each year we removed persons with any evidence of asthma through the end of the year, then identified those with new diagnosis of asthma in the following year. Complementary log-log regression was used to adjust for confounding variables (e.g., sociodemographic, contact with the health system, comorbidities), and hazard ratios (HRs) and 95% confidence intervals (CI) were calculated. RESULTS: A total of 35,441 persons were diagnosed with new onset asthma and were compared to 890,956 persons who did not develop asthma. Persons with new onset asthma tended to be female (69.6%) and younger (mean [SD] age 45.9 [17.0] years). Both CRS definitions were associated (HR, 95% CI) with new onset asthma, with 2.21 (1.93, 2.54) and 1.48 (1.38, 1.59) for CRS based on sinus CT scan and two diagnoses, respectively. New onset asthma was uncommonly observed in persons with a history of sinus surgery. CONCLUSION: Prevalent CRS identified with two complementary approaches was associated with a diagnosis of new onset asthma in the following year. The findings may have clinical implications for the prevention of asthma.

A Bayesian Network Approach to Social and Nonsocial Cognition in Schizophrenia: Are Some Domains More Fundamental than Others?

OBJECTIVES: Social and nonsocial cognition are defined as distinct yet related constructs. However, the relative independence of individual variables-and whether specific tasks directly depend on performance in other tasks-is still unclear. The current study aimed to answer this question by using a Bayesian network approach to explore directional dependencies among social and nonsocial cognitive domains. STUDY DESIGN: The study sample comprised 173 participants with schizophrenia (71.7% male; 28.3% female). Participants completed 5 social cognitive tasks and the MATRICS Consensus Cognitive Battery. We estimated Bayesian networks using directed acyclic graph structures to examine directional dependencies among the variables. STUDY RESULTS: After accounting for negative symptoms and demographic variables, including age and sex, all nonsocial cognitive variables depended on processing speed. More specifically, attention, verbal memory, and reasoning and problem solving solely depended on processing speed, while a causal chain emerged between processing speed and visual memory (processing speed → attention → working memory → visual memory). Social processing variables within social cognition, including emotion in biological motion and empathic accuracy, depended on facial affect identification. CONCLUSIONS: These results suggest that processing speed and facial affect identification are fundamental domains of nonsocial and social cognition, respectively. We outline how these findings could potentially help guide specific interventions that aim to improve social and nonsocial cognition in people with schizophrenia.

Risk of new-onset and prevalent disease in chronic rhinosinusitis: A prospective cohort study.

BACKGROUND: Chronic rhinosinusitis (CRS) is accompanied by burdensome comorbid conditions. Understanding the relative timing of the onset of these conditions could inform disease prevention, detection, and management. OBJECTIVE: To evaluate the association between CRS and new-onset and prevalent asthma, noncystic fibrosis bronchiectasis (NCFBE), chronic obstructive pulmonary disease (COPD), gastroesophageal reflux disease (GERD), and obstructive sleep apnea (OSA). METHODS: We conducted a prospective cohort study among primary care patients using a detailed medical and symptom questionnaire in 2014 and again in 2020. We used questionnaire and electronic health record (EHR) data to determine CRS status: CRSSE (moderate to severe symptoms with EHR evidence), CRSE (limited symptoms with EHR evidence), CRSS (moderate to severe symptoms without EHR evidence), CRSneg (limited symptoms and no EHR evidence; reference). We evaluated the association between CRS status and new-onset and prevalent disease using logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: There were 7847 and 4445 respondents to the 2014 and 2020 questionnaires, respectively. CRSSE (vs CRSneg ) was associated with increased odds of new-onset asthma (OR, 1.74 [CI, 1.09-2.77), NCFBE (OR, 1.87 [CI, 1.12-3.13]), COPD (OR, 1.73 [CI, 1.14-2.68]), GERD (OR, 1.95 [CI, 1.61-2.35]), and OSA (OR, 1.91 [CI, 1.39-2.62]). Similarly, increased odds were observed for associations with the prevalence of these conditions. CONCLUSION: The findings from the study support further exploration of CRS as a target for the prevention and detection of asthma, NCFBE, COPD, GERD, and OSA.

Evidence that oncostatin M synergizes with IL-4 signaling to induce TSLP expression in chronic rhinosinusitis with nasal polyps.

BACKGROUND: Oncostatin M (OSM) may promote type 2 inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP) by inducing thymic stromal lymphopoietin (TSLP). OBJECTIVE: We sought to study the impact of OSM on TSLP synthesis and release from nasal epithelial cells (NECs). METHODS: OSM receptors, IL-4 receptors (IL-4R), and TSLP were evaluated in mucosal tissue and primary NECs from patients with CRSwNP by quantitative PCR and immunofluorescence. Air-liquid interface-cultured NECs were stimulated with cytokines, including OSM, and quantitative PCR, ELISA, Western blot, and flow cytometry were used to assess the expression of OSM receptors, IL-4R, and TSLP. RESULTS: Increased levels of OSM receptor ß chain (OSMRß), IL-4Rα, and TSLP were observed in nasal polyp tissues and primary epithelial cells from nasal polyps of patients with CRSwNP compared with control tissues or cells from control subjects. The level of expression of OSMRß in tissue was correlated with levels of both IL-4Rα and TSLP. OSM stimulation of NECs increased the expression of OSMRß and IL-4Rα. Stimulation with IL-4 plus OSM augmented the production of TSLP; the response was suppressed by a signal transducer and activator of transcription 6 inhibitor. Stimulation of NECs with IL-4 plus OSM increased the expression of proprotein convertase subtilisin/kexin 3, an enzyme that truncates and activates TSLP. CONCLUSIONS: OSM increases the expression of IL-4Rα and synergizes with IL-4 to induce the synthesis and release of TSLP in NECs. Because the combination of IL-4 and OSM also augmented the expression of proprotein convertase subtilisin/kexin 3, these results suggest that OSM can induce both synthesis and posttranslational processing/activation of TSLP, promoting type 2 inflammation.

Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): In-depth sinus surgery analysis.

BACKGROUND: Patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) often require repeat sinus surgery. Mepolizumab reduced the need for sinus surgery in the SYNAPSE trial; this analysis sought to provide a more in-depth assessment of surgery endpoints in SYNAPSE. METHODS: SYNAPSE was a double-blind Phase III trial (NCT03085797) in adults with recurrent, refractory, severe, CRSwNP eligible for repeat sinus surgery despite standard of care treatments and previous surgery. Patients were randomized (1:1) to mepolizumab 100 mg subcutaneously or placebo, plus standard of care, every 4 weeks for 52 weeks. Time to first inclusion on a waiting list for sinus surgery and time to first actual sinus surgery (both up to week 52) were assessed; the latter endpoint was also analyzed post hoc according to time since last sinus surgery before study screening and baseline blood eosinophil count. RESULTS: Among 407 patients (mepolizumab: 206; placebo: 201), mepolizumab versus placebo reduced the risk of being included on a waiting list for sinus surgery (week 52 Kaplan-Meier probability estimate [95% confidence interval]: 13.9% [9.8%, 19.5%] vs. 28.5% [22.7%, 35.4%]). Mepolizumab versus placebo reduced the risk of sinus surgery irrespective of time (<3 vs ≥3 years) since patients' last sinus surgery prior to study screening (hazard ratios [95% confidence intervals] 0.28 [0.09, 0.84] and 0.50 [0.26, 0.98], respectively) and baseline blood eosinophil count. CONCLUSIONS: Mepolizumab reduced the risk of further sinus surgery in patients with recurrent, refractory, severe CRSwNP, irrespective of the patient baseline characteristics assessed.

Persistent discharge or edema after endoscopic sinus surgery in patients with chronic rhinosinusitis is associated with a type 1 or 3 endotype.

BACKGROUND: Patients with chronic rhinosinusitis (CRS) may have persistence of polyps, discharge, or edema after endoscopic sinus surgery (ESS). Inflammation in CRS can be classified into three endotypes, with the presence of polyps associated with the type 2 endotype. Here, we evaluate the endotypic underpinnings of discharge or edema without polyps after ESS. METHODS: At a visit 6-12 months post ESS, patients underwent endoscopy and completed the CRS-PRO and SNOT-22. Luminex analysis of middle meatal mucus obtained at that visit was performed for IFN-γ, ECP, and IL-17a. Type 1, 2, and 3 endotypes were defined as greater than the 90th percentile expression of each marker, respectively, in controls. Wilcoxon rank-sum and chi-squared tests were used to compare cytokine levels and endotype prevalence between those with and without endoscopic findings. RESULTS: A total of 122 CRS patients completed a clinical exam (median: 8.2 months post ESS). Of the 122 patients, 107 did not have polyps on endoscopy. Of these 107 patients, 48 had discharge, 44 had edema, and 46 had neither discharge nor edema. Compared with those patients without any findings, patients with discharge or edema reported significantly worse severity as measured by CRS-PRO (10.5 vs. 7.0, p = 0.009; 12.0 vs. 7.0, p < 0.001; respectively), and had higher post-ESS IFN-γ, ECP, and IL-17a. Patients with discharge had higher prevalence of only T1 and T3 endotypes, while patients with edema had higher prevalence of only the T3 endotype. CONCLUSIONS: Post-ESS discharge or edema in the absence of polyps was associated with higher patient-reported outcome severity and was more strongly associated with type 1 or 3 inflammation.

Patient Perspectives on the Drivers and Deterrents of Antibiotic Treatment of Acute Rhinosinusitis: a Qualitative Study.

BACKGROUND: Antibiotics are prescribed in >80% of outpatient acute rhinosinusitis (ARS) visits, despite the low incidence of bacterial infection. Previous studies have shown patient expectations are the most robust predictor of antibiotics prescription in ARS. However, patient perceptions are not well known or understood. OBJECTIVE: To understand patient perceptions regarding what drives or deters them from wanting, seeking, and taking antibiotic treatment of ARS. DESIGN: Iterative thematic analysis of semi-structured interviews. PARTICIPANTS: Nineteen adults diagnosed with ARS within the prior 60 days at the Northwestern Medicine General Internal Medicine clinic in Chicago, IL. MAIN MEASURES: Perceptions of patients with ARS. KEY RESULTS: We interviewed 19 patients, identifying the following drivers of antibiotic use: (1) symptoms, especially discolored rhinorrhea, and seeking relief, (2) belief that antibiotics are a convenient and/or effective way to relieve/cure sinusitis, and (3) desire for tangible outcomes of a clinic visit. For deterrents, the following themes emerged: (1) concern about antibiotic resistance, (2) preference for other treatments or preference to avoid medications, and (3) desire to avoid a healthcare visit. Patients identified that a trustworthy physician's recommendation for antibiotics was a driver, and a recommendation against antibiotics was a deterrent to taking antibiotics; a delayed antibiotic prescription also served as a deterrent. Antibiotic side effects were viewed neutrally by most participants, though they were a deterrent to some. CONCLUSIONS: Patients have misconceptions about the indications and effectiveness of antibiotics for ARS. Intimate knowledge of key antibiotic drivers and deterrents, from the perspective of patients with ARS, can be leveraged to engage and increase patients' knowledge, and set appropriate expectations for antibiotics for ARS.

The MATRICS Consensus Cognitive Battery: An Update.

Through a series of NIMH-supported consensus-building meetings of experts and empirical comparisons of candidate tests, the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative developed a battery of standardized cognitive measures to allow reliable evaluation of results from clinical trials of promising interventions for core cognitive deficits in this disorder. Ten tests in seven cognitive domains were selected for the MATRICS Consensus Cognitive Battery (MCCB). The MCCB has now been translated into 39 languages/dialects and has been employed in more than 145 clinical trials. It has become the standard cognitive change measure for studies of both pharmacological and training-based interventions seeking to improve cognitive deficits in schizophrenia. We summarize its applications and its relationship to the subsequent development of the NIMH RDoC Matrix.

Comparing the severity of chronic rhinosinusitis symptoms before versus during the COVID-19 pandemic.

Background: COVID-19 measures such as masking, social distancing, and staying indoors may mitigate chronic rhinosinusitis (CRS) symptoms. We evaluate whether these measures correlated with improved symptoms in patients with CRS. Methods: This retrospective study compared SNOT-22 survey data from the Northwestern CRS Registry at the time of enrollment and at years 1-5 of follow-up. The final sample consisted of 1826 SNOT-22 surveys for 598 patients. April 10, 2020 to December 31, 2021 was considered "during the pandemic" and prior to March 11, 2020 was considered "pre-pandemic." Wilcoxon test was used to compare SNOT22 at enrollment pre-pandemic versus during pandemic. Separate linear mixed models were performed to estimate SNOT22 at 1 to 5 years after enrollment pre-pandemic versus during pandemic. Results: Subjects enrolled during the pandemic had worse SNOT22 scores than those enrolled pre-pandemic (53 vs. 42, p = .0024). Total SNOT-22 scores were improved during the pandemic than before the pandemic at 1 year follow-up (18.17 vs. 12.22, p = .001). This effect persists when evaluating the nasal (7.33 vs. 5.13, p = .003), sleep (2.63 vs. 1.39, p = .008), function (1.40 vs. 0.72, p = .015), and emotion (0.77 vs. 0.17, p < .001) domains individually. There was no statistically significant difference in total SNOT-22 score at Years 2-5 of follow-up. Conclusions: Patients with CRS experience a greater reduction in symptom severity in their first year of treatment during the pandemic than before the pandemic, plausibly from measures such as masking and staying indoors. Level of Evidence: 4.

Housing outcomes among homeless-experienced veterans engaged in vocational services.

Though unemployment and homelessness are closely intertwined, vocational services are rarely prioritized for homeless-experienced individuals engaging in housing services. Our goal was to examine associations between vocational service use and housing outcomes among homeless-experienced Veterans engaged in permanent supportive housing. We obtained data from Veterans Health Administration (VHA) medical record and homelessness registry data for homeless-experienced Veterans engaged in U.S. Department of Veterans Affairs (VA) Greater Los Angeles' permanent supportive housing program from October 2016 to September 2017 (n = 1,200). We used multivariate logistic regression to examine whether vocational service use was associated with housing attainment and/or premature permanent supportive housing exits. We found that Veterans in permanent supportive housing who used vocational services were more likely to attain housing (OR = 2.52, p < .001) than their peers who did not use these services. There were no between-group differences in the odds of premature exits from the permanent supportive housing program (OR = 1.92, p = .425). Our study suggests that, among homeless-experienced Veterans engaged in permanent supportive housing programs, those who use vocational services potentially may be more likely to attain housing. However, future research can better elucidate the pathways underlying vocational service use and housing outcomes for individuals in permanent supportive housing programs. Greater integration of vocational services and permanent supportive housing programs, and encouragement of vocational service use may enhance housing outcomes among permanent supportive housing participants. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Retinoic acid promotes fibrinolysis and may regulate polyp formation.

BACKGROUND: Patients with aspirin-exacerbated respiratory disease (AERD) regularly exhibit severe nasal polyposis. Studies suggest that chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by excessive fibrin deposition associated with a profound decrease in epithelial tissue plasminogen activator (tPA). Retinoids, including vitamin A and its active metabolite retinoic acid (RA), are necessary for maintaining epithelial function and well-known inducers of tPA in endothelial cells. OBJECTIVES: This study sought to determine whether endogenous retinoids are involved in NP pathophysiology and disease severity in patients with CRSwNP and AERD. METHODS: NP tissue was collected from patients with AERD or CRSwNP, and concentrations of retinoids and fibrinolysis markers were measured using ELISA. Normal human bronchial epithelial cells were stimulated alone or in combination with RA and IL-13 for 24 hours. RESULTS: This study observed lower retinoid levels in nasal polyps of patients with AERD than those with CRSwNP or healthy controls (P < .01). Levels of the fibrin-breakdown product d-dimer were the lowest in AERD polyps (P < .01), which is consistent with lower tPA expression (P < .01). In vitro, all-trans RA upregulated tPA levels in normal human bronchial epithelial cells by 15-fold and reversed the IL-13-induced attenuation of tPA expression in cultured cells (P < .01). CONCLUSIONS: RA, a potent inducer of epithelial tPA in vitro, is reduced in tissue from patients with AERD, a finding that may potentially contribute to decreased levels of tPA and fibrinolysis in AERD. RA can induce tPA in epithelial cells and can reverse IL-13-induced tPA suppression in vitro, suggesting the potential utility of RA in treating patients with CRSwNP and/or AERD.

Efficacy of an oral CRTH2 antagonist (AZD1981) in the treatment of chronic rhinosinusitis with nasal polyps in adults: A randomized controlled clinical trial.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a type 2 inflammatory disease of the upper airways. AZD1981 is a selective antagonist of chemoattractant receptor-homologous molecule expressed on T helper type 2 and other type 2 cells, including innate lymphoid cells type 2, eosinophils, and basophils. OBJECTIVE: To evaluate the efficacy of AZD1981 in reducing nasal polyp size when added to intranasal corticosteroids in adult patients with CRSwNP. METHODS: Eighty-one subjects (18-70 years of age) with CRSwNP were recruited and screened for trial eligibility from allergy and otolaryngology clinics from a single tertiary care site between June 2016 and August 2019. Eligible patients were randomized in a double-blind fashion to receive either AZD1981 (n = 22) or placebo (n = 21) orally three times a day for 12 weeks, added to intranasal corticosteroids. The primary endpoint was a change in nasal polyp score (NPS) at 12 weeks. Secondary endpoints included improvement in sinus computed tomography using Lund Mackay scoring, symptoms using visual analog scale, quality of life using Sino Nasal Outcome Test-22, and the Brief Smell Identification Test. RESULTS: Forty-three patients met the inclusion criteria and were enrolled. At 12 weeks, there was no difference in NPS change in the AZD1981 arm (mean 0, standard error 0.34, n = 15) compared with placebo (mean 0.20, standard error 0.36, n = 17); mean difference -0.20 (95% confidence interval: -1.21, 0.81; p = .69). No significant differences were observed for Lund Mackay score, symptoms, quality of life, or smell test. AZD1981 was well tolerated except for one case of hypersensitivity reaction. CONCLUSION: In patients with CRSwNP, the addition of AZD1981 to intranasal corticosteroids did not change nasal polyp size, radiographic scores, symptoms, or disease-specific quality of life.

International consensus statement on allergy and rhinology: Olfaction.

BACKGROUND: The literature regarding clinical olfaction, olfactory loss, and olfactory dysfunction has expanded rapidly over the past two decades, with an exponential rise in the past year. There is substantial variability in the quality of this literature and a need to consolidate and critically review the evidence. It is with that aim that we have gathered experts from around the world to produce this International Consensus on Allergy and Rhinology: Olfaction (ICAR:O). METHODS: Using previously described methodology, specific topics were developed relating to olfaction. Each topic was assigned a literature review, evidence-based review, or evidence-based review with recommendations format as dictated by available evidence and scope within the ICAR:O document. Following iterative reviews of each topic, the ICAR:O document was integrated and reviewed by all authors for final consensus. RESULTS: The ICAR:O document reviews nearly 100 separate topics within the realm of olfaction, including diagnosis, epidemiology, disease burden, diagnosis, testing, etiology, treatment, and associated pathologies. CONCLUSION: This critical review of the existing clinical olfaction literature provides much needed insight and clarity into the evaluation, diagnosis, and treatment of patients with olfactory dysfunction, while also clearly delineating gaps in our knowledge and evidence base that we should investigate further.