J. Madison Hyer

Cluster analysis and prediction of treatment outcomes for chronic rhinosinusitis

BACKGROUND Current clinical classifications of chronic rhinosinusitis (CRS) have weak prognostic utility regarding treatment outcomes. Simplified discriminant analysis based on unsupervised clustering has identified novel phenotypic subgroups of CRS, but prognostic utility is unknown. OBJECTIVE We sought to determine whether discriminant analysis allows prognostication in patients choosing surgery versus continued medical management. METHODS A multi-institutional prospective study of patients with CRS in whom initial medical therapy failed who then self-selected continued medical management or surgical treatment was used to separate patients into 5 clusters based on a previously described discriminant analysis using total Sino-Nasal Outcome Test-22 (SNOT-22) score, age, and missed productivity. Patients completed the SNOT-22 at baseline and for 18 months of follow-up. Baseline demographic and objective measures included olfactory testing, computed tomography, and endoscopy scoring. SNOT-22 outcomes for surgical versus continued medical treatment were compared across clusters. RESULTS Data were available on 690 patients. Baseline differences in demographics, comorbidities, objective disease measures, and patient-reported outcomes were similar to previous clustering reports. Three of 5 clusters identified by means of discriminant analysis had improved SNOT-22 outcomes with surgical intervention when compared with continued medical management (surgery was a mean of 21.2 points better across these 3 clusters at 6 months, P < .05). These differences were sustained at 18 months of follow-up. Two of 5 clusters had similar outcomes when comparing surgery with continued medical management. CONCLUSION A simplified discriminant analysis based on 3 common clinical variables is able to cluster patients and provide prognostic information regarding surgical treatment versus continued medical management in patients with CRS.

Identification of chronic rhinosinusitis phenotypes using cluster analysis.

Current clinical classifications of chronic rhinosinusitis (CRS) have been largely defined based upon preconceived notions of factors thought to be important, such as polyp or eosinophil status. Unfortunately, these classification systems have little correlation with symptom severity or treatment outcomes. Unsupervised clustering can be used to identify phenotypic subgroups of CRS patients, describe clinical differences in these clusters and define simple algorithms for classification.

Mucous Cytokine Levels in Chronic Rhinosinusitis-Associated Olfactory Loss

IMPORTANCE Olfactory loss is a frequent symptom of patients with chronic rhinosinusitis (CRS), but our understanding of how inflammatory cytokines affect olfaction is limited. OBJECTIVES To examine whether inflammatory cytokines are present in the olfactory cleft and whether they correlate with objective olfaction. DESIGN, SETTING, AND PARTICIPANTS In this cross-sectional study, patients with CRS underwent quantitative olfactory testing using the Sniffin Sticks test to calculate a composite threshold discrimination identification (TDI) score from October 21, 2013, to November 12, 2015. Nasal mucus was collected using a sponge placed in the olfactory cleft for 5 minutes, and Cytometric Bead Array was used to measure secreted immunomodulatory products. Correlations between TDI score and secreted mediators were then calculated. Data analysis was performed from October 15, 2015, to December 17, 2015. MAIN OUTCOMES AND MEASURES Composite TDI scores and mean secreted mediator levels in mucus from the olfactory cleft. RESULTS Thirty-four patients were enrolled (mean [SD] age, 57.3 [15.7] years; female, 21 [61.8%]; white, 26 [76.5]). The TDI scores were lower in patients with CRS with nasal polyps (CRSwNP) than in patients with CRS without nasal polyps (CRSsNP) (difference, 8.7; 95% CI, 2.5-15.0; P = .007). Interleukin (IL) 5 levels were inversely correlated with TDI scores in patients with CRSwNP and those with CRSsNP (mean [SE] β estimate, -46.56 [15.11]; P = .005), whereas IL-6, IL-7, and vascular endothelial growth factor A were positively correlated with TDI scores only in the CRSwNP cohort. Subscale olfactory TDI scores followed similar correlations to composite TDI scores. CONCLUSIONS AND RELEVANCE In this study, inflammatory cytokines were found in mucus collected from the olfactory cleft. Levels of IL-5, in addition to other cytokines, were associated with objective olfactory function. Further inquiry is needed to establish the source of mucous cytokines and establish whether they play a causal role in olfactory loss.

Depression-Specific Outcomes After Treatment of Chronic Rhinosinusitis

IMPORTANCE Depression is frequently undiagnosed in patients with chronic rhinosinusitis (CRS) and affects quality of life, productivity, and health care use. OBJECTIVE To examine depression-specific outcomes after medical or surgical treatment of CRS. DESIGN, SETTING, AND PARTICIPANTS A multi-institutional, prospective study of patients with refractory CRS treated at tertiary academic rhinology centers was performed from March 1, 2011, to November 1, 2015. Data analysis was performed from October 1, 2015, to November 1, 2015. INTERVENTIONS Patients self-selected to undergo continued medical management or endoscopic sinus surgery for refractory CRS. MAIN OUTCOMES AND MEASURES Patients completed the 22-item Sinonasal Outcome Test (SNOT22), Rhinosinusitis Disability Index (RSDI), Pittsburgh Sleep Quality Index (PSQI), and missed productivity and medication use questionnaires before and at least 6 months after treatment. Computed tomography and endoscopy scoring were performed with reviewers masked to patient-reported data. Depression-specific outcomes were recorded using the 2-item Patient Health Questionnaire (PHQ2). RESULTS Baseline data were available on 685 patients, with 167 (24.4%) having depression according to the PHQ2 scores. The mean (SD) age of the patients was 50.5 (15.0) years, and 332 (48.4%) were male. Revision surgery status was the only baseline factor associated with depression (53.9% vs 38.0%, P < .001). Patients with depression had worse baseline SNOT22 (mean, 64.5 vs 47.6), PSQI (mean, 12.8 vs 8.4), productivity (mean, 22.8 vs 5.2 days missed), and medication use scores for oral antibiotics (mean, 23.8 vs 14.8) and oral corticosteroids (mean, 17.8 vs 9.9) (P < .001 for all). Medical and surgical treatments had similar outcomes for patients with depression with mean improvement in the PHQ2 scores from 3.96 to 1.91 (P < .001), and 110 of 167 patients (65.9%) categorized as having depression at baseline were categorized as not having depression after treatment. Improvements in the PHQ2 scores were associated with improvements in the SNOT22, PSQI, oral antibiotic use, and productivity scores (P ≤ .001 for all). CONCLUSIONS AND RELEVANCE Depression is a common comorbidity in patients with CRS and affects numerous quality-of-life and health care outcomes. There are few objective baseline factors to aid physicians in identifying depression in patients with CRS. Medical and surgical treatments for CRS improve depression and related clinical outcomes.

The Olfactory Cleft Endoscopy Scale correlates with olfactory metrics in patients with chronic rhinosinusitis

Olfactory loss affects a majority of patients with chronic rhinosinusitis (CRS). Traditional objective measures of disease severity, including endoscopy scales, focus upon the paranasal sinuses and often have weak correlation to olfaction.

DUSP1 Phosphatase Regulates the Proinflammatory Milieu in Head and Neck Squamous Cell Carcinoma

DUSP1 is a dual-specificity phosphatase that regulates mitogen-activated protein (MAP) kinase activity. Studies have associated loss of DUSP1 expression with certain cancers, but there has been no report of a mechanism by which this supports tumor progression. In this study, we found DUSP1 mRNA and protein decreased in human head and neck squamous cell carcinoma tissues compared with adjacent nontumor controls. To evaluate the impact of this difference, we compared the susceptibility of Dusp1-deficient mice with oral squamous carcinogenesis induced by 4-nitroquinoline 1-oxide. Dusp1-deficient mice displayed enhanced disease progression, characterized by advanced onset, histologic stage, and tumor burden. In a syngeneic model of tumor progression, subcutaneous injection of EO771 cells formed faster-growing tumors in Dusp1-deficient mice, an effect abrogated by inhibition of p38 MAP kinase with SB203580. Histologic and quantitative assessments demonstrated increased inflammation and deregulated chemokine and cytokine expression in Dusp1-deficient tumor tissues. Specifically, proinflammatory cytokine IL1β was elevated. IL1β production was recapitulated ex vivo in primary bone marrow-derived macrophages from Dusp1-deficient mice. Together, our results clearly establish the role of Dusp1 as a tumor suppressor gene that regulates cancer-associated inflammation.

The Effect of Chronic Kidney Disease on Mortality with Cardiac Resynchronization Therapy.

Cardiac resynchronization therapy (CRT) improves functional status, reduces heart failure hospitalizations, and decreases mortality. Several comorbidities including renal function affect outcomes with CRT. However, moderate to severe chronic kidney disease (CKD) was an exclusion criterion in the large randomized control trials.

Peer-to-Peer Mentoring for African American Women With Lupus: A Feasibility Pilot

To examine the feasibility and potential benefits of peer mentoring to improve the disease self‐management and quality of life of individuals with systemic lupus erythematosus (SLE).

Impact of endogenous progesterone on reactivity to yohimbine and cocaine cues in cocaine-dependent women

Background and objective: Data from clinical and preclinical models of relapse suggest that progesterone attenuates cocaine‐seeking behavior. In a recent study, we found that cocaine‐dependent women reported greater subjective responses to cues that were preceded by a stressor than cocaine‐dependent men. The objective of this study was to examine the impact of endogenous progesterone on the subjective and endocrine responses to a drug‐paired cue that was preceded by a stressor in cocaine‐dependent women. Methods: Cocaine‐dependent women with low (< 4 ng/ml; n = 16) and high (≥ 4 ng/ml; n = 9) plasma progesterone levels received either the alpha‐2 adrenergic receptor antagonist yohimbine (21.6 mg) or placebo before each of two cocaine‐cue exposure sessions. Participants were tested under both conditions in a counterbalanced, double‐blind fashion. Data were collected after study drug administration, immediately and at 5, 30, and 60 min after the cue. Results: The anxiety response to the cue was differentially modified by progesterone levels under the two administration conditions (condition × progesterone level interaction, F1,23 = 9.8, p = 0.005). Progesterone levels also modified the craving response to the cue differently under the placebo condition as compared to the yohimbine condition (condition × progesterone level interaction, F1,23 = 13.9, p = 0.001). In both cases, high progesterone levels attenuated craving and anxiety response to the cue following yohimbine administration. There was no effect of progesterone levels on salivary cortisol or dehydroepiandrosterone under the placebo condition or under the yohimbine condition. Conclusions: These preliminary data suggest that high levels of endogenous progesterone attenuate subjective responses to drug‐cues that are preceded by a stressor. Importantly, these data support a growing literature demonstrating the protective effects of progesterone on the vulnerability to cocaine relapse in women. HIGHLIGHTSWe examined the effect of endogenous progesterone on reactivity following a stressor.High‐progesterone cocaine‐dependent women showed attenuated subjective reactivity.Progesterone may protect against stress‐induced relapse in cocaine‐dependent women.

Predictors of quality of life improvement following peer mentoring in AfricanAmerican women with systemic lupuserythematosus (sle)

Background: Systemic lupus erythematosus is a complex autoimmune disorder with heterogeneous presentation. Behavioral interventions have had mixed effects among this population, particularly among African American women, whom are disproportionately affected. The present study investigates predictors of individual responsiveness to a peer mentoring program designed to provide modeling and reinforcement by peers to African American women with systemic lupus erythematosus. Methods and findings: Potential predictors of outcome in the analyses include sociodemographic variables, psychosocial variables, and self-reported disease symptoms. Changes in patient reported outcomes were calculated between pre- and post-intervention time points. To categorize patients into groups based on level of improvement, a cluster analysis using the Ward’s Minimum Variance method was performed. Statistical comparisons of groups for demographics and patient reported outcomes were performed using Fisher’s exact test or Wilcoxon rank-sum tests. Two disease activity variables significantly predicted individual improvement, whereas other factors assessed had no statistically significant effect. Those mentees with worse self-reported baseline symptom severity (SLAQ2) and disease activity ratings (SLAQ3) had the highest likelihood of improvement. Conclusion: While other factors may influence individual response to the intervention, this analysis stems from a pilot study and may be underpowered to detect them. This subject warrants further study to determine the characteristics of individuals more or less likely to benefit from an intervention so that it can be tailored to their needs. The present data show that individuals with the most severe and active disease may benefit more from an intervention providing social support and targeting their self-management practices.