Trajectories of early-onset rhinitis in the Singapore GUSTO mother-offspring cohort.

BACKGROUND: The natural history of childhood rhinitis is not well described. OBJECTIVE: This study aimed to identify different rhinitis trajectories in early childhood and their predictors and allergic associations. METHODS: Rhinitis symptoms were ascertained prospectively from birth until 6 years using standardized questionnaires in 772 participants. Rhinitis was defined as one or more episodes of sneezing, runny and/or blocked nose >2 weeks duration. Latent trajectories were identified using group-based modelling, and their predictive risk factors and allergic associations were examined. RESULTS: Three rhinitis trajectory groups were identified: 7.6% (n = 59) were termed early transient rhinitis, 8.6% (n = 66) late transient rhinitis, and 6.6% (n = 51) persistent rhinitis. The remaining 77.2% (n = 596) were classified as non-rhinitis/reference group. Early transient rhinitis subjects were more likely of Indian ethnicity, had siblings, reported childcare attendance, early wheezing and eczema in the first 3 years of life. Late transient rhinitis was associated with antenatal exposure to smoking, higher maternal education levels, and wheezing at age 36-72 months. Persistent rhinitis was associated with male gender, paternal and maternal history of atopy, eczema, and house dust mite sensitization. CONCLUSIONS & CLINICAL RELEVANCE: Risk factors for early transient rhinitis involve a combination of genetic and early environmental exposures, whereas late transient rhinitis may relate to maternal factors and early respiratory infections independent of atopy. In contrast, persistent rhinitis is strongly associated with atopic risk and likely represents the typical trajectory associated with allergic disorders. Allergic rhinitis symptoms may commence as early as the first year of life and may inform development of early interventive strategies.

Chronic Rhinosinusitis without Nasal Polyps in Asian Patients Shows Mixed Inflammatory Patterns and Neutrophil-Related Disease Severity.

Chronic rhinosinusitis (CRS) shows heterogeneous immunologic features. Western studies revealed that CRS without nasal polyps (CRSsNP) showed a predominantly type 1 immune response and CRS with nasal polyps (CRSwNP) was characterized by type 2 immune response; however, the detailed immunologic profile of CRSsNP in Asian patients has not been thoroughly investigated. Therefore, we investigated the inflammatory endotypes of CRSsNP in Asian patients. Patients with CRSsNP (N = 57), patients with CRSwNP (N = 13), and a control group (N = 10), who underwent endoscopic sinus surgery, were enrolled; uncinate process (UP) tissues were harvested from all patients. Homogenates were prepared from the UP of each group, and immunologic profiles were analyzed, including major cytokines (32 inflammatory mediators). When comparing the UPs between groups, CRSsNP patients showed higher levels of Th2 cytokines (IL-4 and IL-13), eosinophilic chemokines (CCL-11 and CCL-24), ECP, and total IgE expression than control subjects. In addition, several neutrophilic markers (IL-1α, IL-6, IL-8, CXCL-1, CXCL-2, and MPO), IL-17A, IL-22, and TNF-α were dominant in CRSsNP patients. Among these inflammatory mediators, IL-17A showed higher expression levels in CRSsNP patients than in the control group and CRSwNP patients. However, IFN-γ expression was not significantly elevated in CRSsNP patients. The levels of neutrophil-associated cytokines were well correlated with each other; of which, CXCL2, IL-8, and MMP-9/TIMP-1 levels were significantly correlated with disease extent (r = 0.338, r = 0.317, and r = 0.424, respectively). However, the levels of eosinophil-associated cytokines showed little correlation with each other and were not correlated with disease extent. Our study revealed that Asian CRSsNP patients showed a mixed (types 2 and 17) immune response, but neutrophil-related markers were dominant and associated with disease extent. Knowledge of this immunologic feature may help clinicians make better individual treatment decisions for Asian CRSsNP patients.

Endotypes of Chronic Rhinosinusitis Across Ancestry and Geographic Regions.

PURPOSE OF REVIEW: Preliminary studies have suggested differences in endotypes of chronic rhinosinusitis (CRS) across ancestry/ethnic groups. Eosinophilic CRS (ECRS) is the predominant subtype for Western/European ancestry CRS patients and non-eosinophilic CRS (nECRS) for Asian patients. This review aims to re-analyze CRS endotypes across ancestry populations using one consistent criteria to existing data. RECENT FINDINGS: Although tissue eosinophilia is the most commonly used criterion for ECRS, various cut-off points are suggested. Surrogate markers have been extensively studied. Sixty-six cohorts with study criteria were included with a total of 8557 patients. Raw data from 11 studies 544 patients were re-analyzed using number of tissue eosinophils. At lower cut-off values of ≥ 5 and ≥ 10 cells/HPF, most patients of Asian and Western/European ancestry were classified as ECRS without difference. In contrast, at cut-off points of ≥ 70 and ≥ 120 cells/HPF, the majority of both groups became reclassified as nECRS. After applying one consistent criteria to existing data, differences across ancestry and geographic populations in endotypes of CRS were no longer evident.

Incidence and Burden of Wheezing Disorders, Eczema, and Rhinitis in Children: findings from the Born in Bradford Cohort.

BACKGROUND: Bradford city has high infant mortality and there is a major health concern in the community due to environmental pollution. The aim of the study was to investigate the incidence and burden of wheezing disorders, eczema, and rhinitis in children aged 3-7 years . METHODS: It is a prospective cohort study; the participants were 13 734 children from the Born in Bradford cohort. RESULTS: There were a total of 22.1% (95% Confidence Interval (CI) 21.4, 22.8%), 52.4% (95% CI 51.5%, 53.2%), and 19.3% (95% CI 18.6, 19.9%) incidence cases of wheezing disorders, eczema, and rhinitis respectively. A total of 37% (95% CI 36.2%, 37.8%), 19.5% (95% CI 18.9%, 20.2%,) and 5.9% (95% CI 5.5%, 6.3%) of the children were affected by only one, two, and three diseases respectively. Boys to girls incidence rate ratios for wheezing disorders, eczema, and rhinitis was 1.41 (95% CI 1.31, 1.51), 1.02 (95% CI 0.97, 1.07), and 1.18 (95% CI 1.09, 1.28) respectively. The respective incidence rate ratios of Pakistani to White British were 0.94 (95% CI 0.87, 1.02), 1.31 (95% CI 1.24, 1.39), and 2.03 (95% CI 1.83, 2.25) respectively. CONCLUSION: This study shows that the burden of wheezing disorders, eczema, and rhinitis in this cohort is higher than previously reported in earlier studies. In addition, it indicates that while boys are more likely to suffer from wheezing disorders, rhinitis, and multiple diseases than girls, Pakistani children are more likely to suffer from eczema, rhinitis, and multiple diseases than White British children.

Chronic rhinosinusitis: epidemiology and cost.

Chronic rhinosinusitis (CRS) is one of the most common chronic diseases and is associated with a high socioeconomic burden from direct and indirect costs. Its estimated prevalence ranges widely, from 2 to 16%. It is more common in female subjects, aged 18-64 years, and in southern and midwestern regions of the United States. CRS is more prevalent in patients with comorbid diseases such as asthma, chronic obstructive pulmonary disease, and environmental allergies. Few studies examine patient ethnicity, socioeconomic status, geographic location, and cultural factors in CRS populations. This article provides an overview of the epidemiology, racial variations, and economic burden of CRS.

Epidemiologic factors and surgical outcomes in patients with nasal polyposis and asthma.

BACKGROUND/AIM: To evaluate the role of epidemiologic factors in surgical outcomes for patients with nasal polyposis (NP) and asthma. METHODS: Data was prospectively collected on patients who underwent endoscopic sinus surgery over a 7-year period. Among patients with chronic rhinosinusitis (CRS) with NP and asthma, surgical outcomes were analyzed according to gender and race. RESULTS: Patients with NP and asthma had significantly higher Lund-Kennedy and SNOT-20 scores--pre- and postoperatively--compared to CRS patients without NP or asthma. Both Caucasians and African-Americans in the CRS with NP/asthma group showed a statistically significant improvement at 6 months. Caucasians continued to have a significant improvement at 12 months, whereas African-Americans did not. There were no differences according to gender. CONCLUSION: In our patient population, African-Americans with NP and asthma had poorer outcomes following functional endoscopic sinus surgery.

Plasma RANTES and eotaxin levels are correlated with the severity of chronic rhinosinusitis.

Eosinophilia occurs in up to 75-90% of nasal polyps in Caucasians. The chemokines eotaxin and RANTES increase eosinophil recruitment, activation, and survival, and these chemokines are significantly expressed in nasal polyps. We hypothesized that eotaxin and RANTES plasma levels might be correlated with disease severity. We compared the eotaxin and RANTES plasma levels in 20 Taiwanese patients with chronic rhinosinusitis and nasal polyps and 20 Taiwanese healthy controls. Eotaxin and RANTES plasma levels were measured by ELISA and disease severity was scored by CT scans. Compared to controls, patients with nasal polyps had significantly elevated plasma levels of eotaxin and RANTES and increased peripheral blood eosinophils (p < 0.001). Eotaxin plasma levels were significantly correlated with disease severity in patients with chronic rhinosinusitis to a greater extent than were RANTES levels. RANTES and eotaxin levels were also positively correlated with the percentages of peripheral blood eosinophils. Eotaxin plasma levels are significantly correlated with disease severity in Taiwanese patients with nasal polyposis to a greater degree than are RANTES levels. Additional studies are needed to assess whether eotaxin plasma levels can be used to monitor disease progression and attenuation.

Genetic variation in BDNF is associated with allergic asthma and allergic rhinitis in an ethnic Chinese population in Singapore.

Allergic diseases affect more than 25% of the world population and result from a complex interplay between genetic and environmental factors. Recent evidence has shown that BDNF (Brain Derived Neurotrophic Factor) could serve as an important marker of allergic disease. Increased levels of BDNF in blood, bronchoalveolar lavage fluid and nasal lavage fluid positively correlate with disease activity and severity in patients with allergic rhinitis (AR), asthma and atopic eczema. However, reports on the association between genetic variation in BDNF and allergic disease have been controversial. This study therefore aims to clarify the relationship between single nucleotide polymorphisms (SNPs) in BDNF and a genetic predisposition to AR and asthma in an ethnic Chinese population of Singapore. Volunteers with a self-reported history of asthma (718 subjects) or a history of AR as determined by a researcher-administered questionnaire (795 subjects) were used in this study, alongside controls with no personal or family history of allergy (717 subjects). The association results identified a significant association for the tagSNP rs10767664 with a significant PDominant=0.0007 and OR=1.3 for AR and PDominant=0.0005 and OR=1.3 for asthma (using a dominant model of association). The haplotype based analysis also identified a significant association further confirming the single SNP association. The SNP rs10767664 is strongly linked (r2=0.95) to the functional polymorphism rs6265 (Val66Met), which has previously been reported to be associated to allergic phenotypes and also shown to affect BDNF expression. BDNF is a therefore a key molecular player in allergy. Further studies on polymorphisms within BDNF may shed light on its role in the pathogenesis of allergic diseases and potentially serve as biomarkers for allergic disease.

Smoking, longer disease duration and absence of rhinosinusitis are related to fixed airway obstruction in Koreans with severe asthma: findings from the COREA study.

BACKGROUND: The clinical manifestations of severe asthma are heterogeneous. Some individuals with severe asthma develop irreversible fixed airway obstruction, which is associated with poor outcomes. We therefore investigated the factors associated with fixed airway obstruction in Korean patients with severe asthma. METHODS: Severe asthma patients from a Korean adult asthma cohort were divided into two groups according to the results of serial pulmonary function tests. One group had fixed airway obstruction (FAO) [forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio < 0.7, n = 119] and the other had reversible airway obstruction (RAO) [FEV1/FVC ratio ≥ 0.7, n = 116]. Clinical and demographic parameters were compared between the two groups. RESULTS: Multivariate analysis showed that longer duration of disease, greater amount of cigarette smoking and absence of rhinosinusitis were significantly related to the development of FAO in severe asthmatics. Other parameters, including atopic status, pattern of airway inflammatory cells in induced sputum, and frequency of asthma exacerbations did not differ between the FAO and RAO groups. CONCLUSION: Severe asthma patients with longer disease duration and the absence of rhinosinusitis are more likely to develop FAO. This study also demonstrates the importance of quitting smoking in order to prevent irreversible airway obstruction. Further investigation is required to determine the mechanism by which these factors can modify the disease course in Korean patients with severe asthma.

Race in Rhinology Clinical Trials: A Decade of Disparity.

OBJECTIVE/HYPOTHESIS: The aim of this study is to assess the ethnic and racial demographics of patients enrolled in prospective chronic rhinosinusitis (CRS) studies relative to the corresponding geographic demographics of the United States (U.S.) census data. STUDY DESIGN: Systematic Review and Population analysis. METHODS: A systematic review was performed to identify CRS clinical trials, conducted in the U.S. and published between 2010 and 2020 in which patients were prospectively enrolled. Pooled racial and ethnicity data were compared to national and corresponding regional census data. RESULTS: Eighty-three studies were included, comprising 12,027 patients. 50.4% were male and the average age was 49.2 years. 8,810 patients underwent a surgical procedure. Of the 12,027 patients, 81.67% were identified as White, 5.35% as Black, 1.27% as Asian, 0.02% as Pacific Islander, 0.12% as American Indian, and 11.57% were classified as Other. The racial and ethnic composition of the pooled study population differs significantly from the national U.S. census data with the underrepresentation of each minority population (P ≤ .0002). Regional sub-analyses yield variable results. In the Northeast and West, there was an underrepresentation of all minority populations. In the South and Midwest, Black enrollment was similar to the U.S. census data, while all other minorities were underrepresented. CONCLUSIONS: The racial and ethnic composition of patients enrolled in prospective CRS clinical trials differs significantly from the demographics of the U.S. POPULATION: The generalizability and external validity of findings derived from studies comprised of demographically mismatched populations has not been established. Future efforts to enroll more representative populations should be emphasized by the research community, funding bodies, and editorial boards. LEVEL OF EVIDENCE: NA Laryngoscope, 131:1722-1728, 2021.

The impact of race and insurance status on baseline histopathology profile in patients with chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is an inflammatory disease process characterized by different phenotypes and histopathology profiles. Race and access to care have been implicated in CRS disease severity. Structural histopathology reporting may aid in delineating the inflammatory burden responsible for this effect. METHODS: A structured histopathology report of 14 variables was utilized to assess sinus tissue removed during functional endoscopic sinus surgery (FESS). Histopathology variables and 22-item Sino-Nasal Outcome Test (SNOT-22) scores were compared by race (Black, White, Latino, and Asian) and insurance status (Medicare, Medicaid, and private insurance). RESULTS: A total of 201 CRS patients (124 White, 38 Black, 28 Latino, and 9 Asian) undergoing FESS were included. Black patients demonstrated increased SNOT-22 scores (50.74 ± 20.32 vs 41.47 ± 22.75, p < 0.022) and number of eosinophils per high-power field (>5/HPF) (60.5% vs 44.8%, p < 0.05). White patients demonstrated decreased eosinophil aggregates (22.6% vs 35.1%, p < 0.039) and eosinophils/HPF (<5/HPF) (42.7% vs 55.8%, p < 0.048). Medicaid patients showed increased SNOT-22 score (55.50 ± 24.46 vs 41.39 ± 21.74, p < 0.003), polypoid disease (61.5% vs 42.3%, p < 0.05), subepithelial edema (80.8% vs 53.1%, p < 0.006), hyperplastic/papillary changes (23.1% vs 8.0%, p < 0.028), fibrosis (61.5% vs 38.5%, p < 0.036), eosinophil aggregates (46.2% vs 24.6%, p < 0.022), and eosinophils/HPF (>5/HPF) (65.4% vs 45.1%, p < 0.043). When controlling for insurance status, Black race was no longer associated with increased SNOT-22 (p < 0.104) or eosinophils/HPF (>5/HPF) (p < 0.183). CONCLUSION: Black and Medicaid patients demonstrated more severe disease by histopathology and SNOT-22 scores. These findings were no longer significant among Black patients after adjusting for insurance status, suggesting that the prevailing factor influencing worse disease may be access to care.

Association of Socioeconomic Status, Race and Insurance Status with Chronic Rhinosinusitis Patient-Reported Outcome Measures.

Objective Disparities in health and health care access are widely prevalent. However, disparities among patients with chronic rhinosinusitis (CRS) are poorly understood. We investigated if CRS severity at presentation according to socioeconomic factors. Study Design Cross-sectional study. Setting Tertiary rhinology center. Subjects and Methods Three hundred prospectively recruited patients presenting with CRS were included. Outcome variables included CRS symptomatology, as reflected by the 22-item Sinonasal Outcome Test (SNOT-22); general health status, as reflected by the EuroQol 5-dimensional visual analog scale (EQ-5D VAS); and CRS-related antibiotic and systemic corticosteroid use. Race/ethnicity, zip code income bracket, education level, and insurance status were used as predictor variables. Regression, controlling for clinical and demographic characteristics, was used to determine associations between predictor and outcome variables. Results Mean SNOT-22 score was 33.8 (SD, 23.2), and mean EQ-5D VAS score was 74.2 (SD, 18.9). On multivariable analysis, presenting SNOT-22 and EQ-5D VAS scores were not associated with nonwhite patient race/ethnicity ( P = .634 and P = .866), education ( P = .106 and P = .586), or the percentage of households in zip code with incomes <$50,000 per year ( P = .917 and P = .979, respectively). SNOT-22 scores did not differ by insurance type, but patients receiving Medicare reported worse general health status. Use of oral antibiotics or oral steroids for CRS was not associated with predictor variables. Conclusion Patients with CRS presented to a tertiary rhinology center with similar metrics for CRS severity and pre-presentation medical management regardless of race/ethnicity, education status, or zip code income level. Patients with Medicare had worse general health status. Further research should investigate potential disparities in diagnosis of CRS, specialist referral, and treatment outcomes.

Prevalence of asthma, rhinitis, and eczema among children in Vientiane city, Lao PDR.

An International Study of Asthma and Allergy in Childhood (ISAAC) revealed a wide range of prevalences of childhood asthma in the world. Lao PDR had no such epidemiological data yet. This study aimed to investigate the epidemiology of asthma, rhinitis, and eczema in children in the country. A cross-sectional study was conducted in Vientiane City, the capital of Lao PDR, in 1997 using the ISAAC questionnaire. From three primary schools and one high school, 395 children, age 6-7 years, and 468 children, age 13-14 years, were chosen. The prevalence of asthma for children aged 13-14 years in Lao PDR was 25.6%, which ranks the highest in international asthma prevalence. The prevalence in allergic-rhinoconjunctivitis of children was 24.4% and atopic eczema was 7.1%. Contrary to generally accepted risk factors, there were no associations revealed between asthma prevalence and smoking of family members (especially mothers), intake of fish/meat, and male gender.

Sino-Nasal Outcome Test-22: Translation, Cross-cultural Adaptation, and Validation in Hebrew-Speaking Patients.

OBJECTIVE: To perform the translation, cross-cultural adaptation, and validation of the Sino-Nasal Outcome Test-22 (SNOT-22) questionnaire to the Hebrew language. STUDY DESIGN AND SETTING: A single-center prospective cross-sectional study. SUBJECTS AND METHODS: Seventy-three chronic rhinosinusitis (CRS) patients and 73 patients without sinonasal disease filled the Hebrew version of the SNOT-22 questionnaire. Fifty-one CRS patients underwent endoscopic sinus surgery, out of which 28 filled a postoperative questionnaire. Seventy-three healthy volunteers without sinonasal disease also answered the questionnaire. Internal consistency, test-retest reproducibility, validity, and responsiveness of the questionnaire were evaluated. RESULTS: Questionnaire reliability was excellent, with a high internal consistency (Cronbach's alpha coefficient, 0.91-0.936) and test-retest reproducibility (Spearman's coefficient, 0.962). Mean scores for the preoperative, postoperative, and control groups were 50.44, 29.64, and 13.15, respectively (P < .0001 for CRS vs controls, P < .001 for preoperative vs postoperative), showing validity and responsiveness of the questionnaire. CONCLUSION: The Hebrew version of SNOT-22 questionnaire is a valid outcome measure for patients with CRS with or without nasal polyps.

Presentation to Emergency Departments for Acute Rhinosinusitis: Disparities in Symptoms by Race and Insurance Status.

OBJECTIVE: Medicaid and self-pay insurance statuses and race are associated with emergency department (ED) presentation for uncomplicated acute rhinosinusitis (ARS). We investigated whether ARS symptomatology could explain this disproportionate ED use. STUDY DESIGN: 2006-2010 National Hospital Ambulatory Medical Care Surveys. SETTING: EDs in the United States. SUBJECTS AND METHODS: The data comprise 1,632,826 adult visits for uncomplicated ARS at hospital EDs. Patient-reported reasons for presentation included constitutional symptoms, facial pain or headache, sinonasal symptoms, head cold or flu-like symptoms, cough or sputum production, and sore throat. Patient-reported pain level was also included. Symptoms were assessed for associations with insurance status and race after controlling for clinical, demographic, and socioeconomic characteristics. RESULTS: Medicaid patients had similar symptomatology and levels of pain when compared with privately insured patients. Self-pay patients reported higher pain levels (P = .033) and were less likely to report head cold or flu-like symptoms (P = .018) but were equally likely to report other symptomatology. Relative to white patients, Hispanic patients were more likely to complain of facial pain and headaches (P = .033) and less likely to complain of other classical ARS symptoms, such as cough or sputum production (P = .013), sinonasal symptoms (P = .019), or head cold or flu-like symptoms (P = .019). Black patients were also less likely to complain of sinonasal symptoms (P = .038). CONCLUSION: Symptomatology does not explain disproportionate ED use for ARS by Medicaid patients, while higher self-reported pain levels may explain self-pay patients' disproportionate ED utilization. Likewise, ED presentation for ARS among Hispanic patients may be related to symptomatology that is less specific for ARS, such as headache and facial pain.

Epidemiology of bronchial asthma and chronic rhinitis in schoolchildren of different ethnic origins from two neighboring towns in Israel.

Allergic diseases have increased significantly in developed countries for reasons yet to be determined. We studied the epidemiology of bronchial asthma (B.A.) and chronic rhinitis (Ch.R.) among Israeli school children from two neighboring towns, one Jewish (Zichron Yaakov, school population = 585) and the other Arab (Paradis, school population = 658). The children (age range 8-17 years, 567 males, 676 females) shared the same climate and had similar demographic characteristics. They received similar medical care and had the same rates of hospitalization and emergency room visits. The Jewish children had a higher prevalence of B.A. (13.7% vs. 9.4%), Ch.R. (19.7% vs. 9.7%), and stuffy nose (31% vs. 14%) than their Arab counterparts. In addition to ethnicity, parental smoking habits were the major differentiating factor between the two groups: 20% of the mothers and 29% of the fathers from Zichron Yaakov and 2% of the mothers and 60% of the fathers from Paradis were smokers. Smoking fathers increased the rate of B.A. in both towns as well as emergency room visits, but not the rate of Ch.R. or stuffy nose. A familial history of B.A. was the main determinant for having childhood asthma or chronic rhinitis. We conclude that in addition to family history and ethnicity, smoking among mothers was the major contributing factor for the higher prevalence of atopic diseases among Jewish schoolchildren compared to their Arab counterparts.

Chronic rhinosinusitis, race, and ethnicity.

BACKGROUND: Little is known regarding the epidemiology of chronic rhinosinusitis (CRS) in racial and ethnic minorities in the United States. This study was designed to comprehensively evaluate the current prevalence of CRS across various treatment settings to identify possible disparities in health care access and use between racial and ethnic populations. METHODS: The National Health Interview Survey (NHIS), National Ambulatory Medical Care Survey (NAMCS), and National Hospital Ambulatory Medical Care Survey (NHAMCS) database registries were extracted to identify the national prevalence of CRS in race/ethnic populations and resource use in ambulatory care settings. Systematic literature review identified studies reporting treatment outcomes in minority patients electing endoscopic sinus surgery (ESS). Data were supplemented using a multi-institutional cohort of patients undergoing surgical treatment. RESULTS: National survey data suggest CRS is a significant health condition for all major race/ethnic groups in the United States, accounting for a sizable portion of office, emergency, and outpatient visits. Differences in insurance status, work absenteeism, and resource use were found between race/ethnic groups. Despite its prevalence, few published studies include information regarding minority patients with CRS. Most (90%) cohort studies did not provide details of race/ethnicity for ESS outcomes. Prospective cohort analysis indicated that minority surgical patients accounted for only 18%, when compared with national census estimates (35%). CONCLUSION: CRS is an important health condition for all major race/ethnic groups in the United States. Significant differences may exist across racial and ethnic categories with regard to CRS health status and health care use. Given current demographic shifts in the United States, specific attention should be given to understanding CRS within the context of racial and ethnic populations. Public clinical trial registration (www.clinicaltrials.gov) I.D. No. NCT00799097.