Relationships between symptoms and lung function in asthma and/or chronic obstructive pulmonary disease in a real-life setting: the NOVEL observational longiTudinal studY.

BACKGROUND: The relationships between spirometric assessment of lung function and symptoms (including exacerbations) in patients with asthma and/or chronic obstructive pulmonary disease (COPD) in a real-life setting are uncertain. OBJECTIVES: To assess the relationships between baseline post-bronchodilator (post-BD) spirometry measures of lung function and symptoms and exacerbations in patients with a physician-assigned diagnosis of asthma and/or COPD. DESIGN: The NOVEL observational longiTudinal studY (NOVELTY) is a global, prospective, 3-year observational study. METHODS: Logistic regression analysis was used to evaluate relationships. Spirometry measures were assessed as percent predicted (%pred). Symptoms were assessed at baseline, and exacerbations were assessed at baseline and Year 1. RESULTS: A total of 11,181 patients in NOVELTY had spirometry data (asthma, n = 5903; COPD, n = 3881; asthma + COPD, n = 1397). A 10% lower post-BD %pred forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) - adjusted for age and sex - were significantly associated with dyspnea (modified Medical Research Council ⩾ grade 2), frequent breathlessness [St George's Respiratory Questionnaire (SGRQ)], frequent wheeze attacks (SGRQ), nocturnal awakening (Respiratory Symptoms Questionnaire; ⩾1 night/week), and frequent productive cough (SGRQ). Lower post-BD %pred FEV1 and, to a lesser extent, lower post-BD %pred FVC were significantly associated with ⩾1 physician-reported exacerbation at baseline or Year 1. This association was stronger in patients with COPD than in those with asthma. CONCLUSION: In a real-life setting, reduced lung function is consistently associated with symptoms in patients with asthma, COPD, or asthma + COPD. The relationship with exacerbations is stronger in COPD only than in asthma. TRAIL REGISTRATION: clinicaltrials.gov identifier: NCT02760329 (www.clinicaltrials.gov).

Relationships between symptoms and lung function in asthma and/or chronic obstructive pulmonary disease in a study performed in a real-life setting: the NOVELTY studyBackground: Asthma and chronic obstructive pulmonary disease (COPD) have many symptoms in common. To confirm diagnosis, doctors use spirometry, a test to measure the amount of air that can be breathed out from the lungs and how fast it can be blown out. The relationship between these measurements and symptoms in asthma and COPD is not well understood.Objectives: The aim of this research is to describe the characteristics, treatment, and impact of asthma and/or COPD in patients who are receiving their usual medical care.Methods: NOVELTY is a large study of around 12,000 patients across 19 countries. This analysis of NOVELTY looked at the relationships between two spirometry measurements and the symptoms of asthma and/or COPD experienced by patients. The spirometry measurements were: - forced expiratory volume in 1 second (FEV₁) ­ the amount of air that can be blown out of the lungs in 1 second- forced vital capacity (FVC) ­ the amount of air that can be forcibly breathed out from the lungs after taking the deepest breath possibleResults: The lower the FEV₁ and FVC, the more common the symptoms of breathlessness, wheeze attacks, night-time awakening, and coughing up of phlegm or mucus. These relationships were similar for FEV₁ and FVC. Lower FEV₁ was more strongly associated with worse symptoms in COPD than in asthma.Conclusion: These findings help to improve our understanding of the relationships between spirometry measures and symptoms in patients with asthma and/or COPD.

Albuterol-budesonide fixed-dose combination rescue inhaler for asthma: a plain language summary of the MANDALA study.

What is this summary about?This summary describes the results of a clinical study called MANDALA that was published in the New England Journal of Medicine in 2022. In the MANDALA study, researchers looked at a new asthma rescue inhaler that contains both albuterol and budesonide in a single inhaler (known as albuterol-budesonide, AIRSUPRA™). This summary describes the results for people aged 18 yearsand older who took part in the study.

Impact of Clinical Characteristics and Biomarkers on Asthma Impairment and Risk Questionnaire Exacerbation Prediction Ability.

BACKGROUND: Complex models combining impairment-based control assessments with clinical characteristics and biomarkers have been developed to predict asthma exacerbations. The composite Asthma Impairment and Risk Questionnaire (AIRQ) with adjustments for demographics (age, sex, race, and body mass index) predicts 12-month exacerbation occurrence similarly to these more complex models. OBJECTIVE: To examine whether AIRQ exacerbation prediction is enhanced when models are adjusted for a wider range of clinical characteristics and biomarkers. METHODS: Patients aged 12 years and older completed monthly online surveys regarding exacerbation-related oral corticosteroid use, emergency department or urgent care visits, and hospitalizations. Univariate logistic regressions to predict exacerbations were performed with sociodemographics, comorbidities, exacerbation history, lung function, blood eosinophils, IgE, and FeNO. Significant (P ≤ .05) variables were included in multivariable logistic regressions with and without AIRQ control categories to predict 12-month exacerbations (log odds ratio [95% Wald confidence interval]). Model performances were compared. RESULTS: Over 12 months, 1,070 patients (70% female; mean [SD] age, 43.9 [19.4] years; 22% non-White; body mass index [SD], 30.6 [8.7]) completed one or more survey (mean [SD], 10.5 [2.8] surveys). In the multivariable analysis, AIRQ control category adjusted for significant clinical characteristics and biomarkers was predictive of one or more exacerbations: odds ratio (95% CI) not well-controlled versus well-controlled: 1.93 (1.41-2.62), very poorly controlled versus well-controlled: 3.81 (2.65-5.47). Receiver operating characteristic area under the curve (AUC) for this more complex model of exacerbation prediction (AUC = 0.72) did not differ from AIRQ (AUC = 0.70). Models with AIRQ performed better than those without AIRQ (AUC = 0.67; P < .05). CONCLUSION: Costly and time-consuming complex modeling with clinical characteristics and biomarkers does not enhance the strong exacerbation prediction ability of AIRQ.

Quality of Life Improvements with Biologic Initiation Among Subspecialist-Treated US Patients with Severe Asthma.

Purpose: Patients living with severe asthma (SA) experience multiple health-related quality of life (HRQoL) impairments. This study examined HRQoL changes after biologic treatment initiation among a large, real-world cohort of patients with SA. Patients and methods: CHRONICLE is an ongoing observational study of subspecialist-treated adults with SA who receive biologics or maintenance systemic corticosteroids or are uncontrolled on high-dosage inhaled corticosteroids with additional controllers. Patients enrolled February 2018-February 2023 were asked to complete the St. George's Respiratory Questionnaire (SGRQ) every 6 months (total score range of 0-100 [0=best possible health], meaningful change threshold is a 4-unit reduction in the total score). Changes in SGRQ responses from 6 months before initiation to 12 to 18 months after initiation were summarized. Results: A total of 76 patients completed the SGRQ 0 to 6 months before and 12 to 18 months after biologic initiation. The mean (SD) SGRQ total score decreased from 52.2 (20.6) to 41.9 (23.8), with improvement across the symptoms (-14.5), activity (-11.0), and impacts (-8.3) components. For specific impairments reported by ≥50% of patients before biologic initiation, fewer reported each impairment after biologic initiation; the largest reductions were for "Questions about what activities usually make you feel short of breath these days [Walking outside on level ground]" (67% to 43%), "Questions about other effects that your respiratory problems may have on you these days [I feel that I am not in control of my respiratory problems]" (55% to 34%), and "Questions about your cough and shortness of breath these days [My coughing or breathing disturbs my sleep]" (63% to 45%). Conclusion: In this real-world cohort of adults with SA, biologic initiation was associated with meaningful improvements in asthma-related HRQoL. These data provide further insight into the burden SA places on patients and the benefits of biologic treatment.

Advancing assessment of asthma control with a composite tool: The Asthma Impairment and Risk Questionnaire.

BACKGROUND: National and international asthma guidelines and reports do not include control tools that combine impairment assessment with exacerbation history in one instrument. OBJECTIVE: To analyze the performance of the composite Asthma Impairment and Risk Questionnaire (AIRQ) in assessing both domains of control and predicting exacerbation risk compared with the Global Initiative for Asthma (GINA) 4-question symptom control tool (GINA SCT), Asthma Control Test (ACT), and physician expert opinion (EO) informed by GINA SCT responses and appraisal of GINA-identified risk factors for poor asthma outcomes. METHODS: Multivariable logistic regressions evaluated AIRQ and GINA SCT as predictors of ACT. McNemar's test compared the proportion of patients categorized at baseline as completely or well-controlled by each assessment but with current impairment or previous-year and subsequent-year exacerbations. RESULTS: The analysis included 1064 patients aged 12 years or older; mean (SD) age 43.8 years (19.3); 70% female; 79% White; and 6% Hispanic or Latino. AIRQ and GINA SCT were highly predictive of ACT well-controlled vs not well-controlled and very poorly controlled (receiver operator characteristic area under curve AIRQ = 0.90, GINA SCT = 0.86, P = .03 AIRQ vs GINA SCT) and ACT very poorly controlled vs well-controlled and not well-controlled asthma (receiver operator characteristic area under curve AIRQ = 0.91, GINA SCT = 0.87, P = .01 AIRQ vs GINA SCT). AIRQ rated fewer patients as having completely or well-controlled asthma who had current impairment (P < .01) or with previous-year and subsequent-year exacerbations (P < .001) than did GINA SCT, ACT, and EO. CONCLUSION: AIRQ performs better in assessing both domains of current control and predicting exacerbation risk than do control tools and EO informed by GINA SCT and risk factors for poor asthma outcomes.

The Use of Albuterol/Budesonide as Reliever Therapy to Reduce Asthma Exacerbations.

Prevention of asthma exacerbations and reduction of systemic corticosteroid burden remain unmet needs in asthma. US asthma guidelines recommend concomitant short-acting ß2-agonist (SABA) and inhaled corticosteroid (ICS) as an alternative reliever at step 2. The Food and Drug Administration approved a pressurized metered-dose inhaler containing albuterol and budesonide for as-needed treatment or prevention of bronchoconstriction and for reducing exacerbation risk in patients with asthma aged ≥18 years. This combination is approved for use as a reliever with or without maintenance therapy, but it is not indicated for maintenance therapy (or for single maintenance and reliever therapy). Intervening with as-needed SABA-ICS during the window of opportunity to reduce inflammation during loss of asthma control can reduce exacerbation risk, by exerting both genomic and nongenomic anti-inflammatory effects. We propose that the use of albuterol-budesonide rather than albuterol as a reliever to manage episodic symptoms driven by acute bronchoconstriction and airway inflammation can improve outcomes. This combination approach, shown to decrease asthma exacerbations and oral corticosteroid burden in patients with moderate-to-severe asthma, represents a paradigm shift for asthma treatment in the United States. Further safety and efficacy studies should provide evidence that this type of reliever should be standard of care.

Real-world effectiveness of benralizumab in US subspecialist-treated adults with severe asthma: Findings from CHRONICLE.

BACKGROUND: Patients with eosinophilic severe asthma (SA) have an increased risk of asthma exacerbations. Benralizumab is approved for eosinophilic SA, and there is great value in understanding real-world effectiveness. OBJECTIVE: The aim of this analysis was to examine the effectiveness of benralizumab in a real-world cohort of subspecialist-treated US patients with eosinophilic SA. METHODS: CHRONICLE is an ongoing, noninterventional study of subspecialist-treated US adults with SA receiving biologics, maintenance systemic corticosteroids, or those persistently uncontrolled by high-dose inhaled corticosteroids with additional controllers. For this analysis, eligible patients enrolled from February 2018 to February 2021, had received ≥ 1 dose of benralizumab, and had study data for ≥ 3 months before and after benralizumab initiation. The primary analysis included patients with prior exacerbations reported and 12 months of outcomes data before and after initiation. Patient outcomes occurring 6-12 months before and after initiation were also evaluated. RESULTS: A total of 317 patients had ≥ 3 months of follow-up before and after first benralizumab dose. For patients with 12 months (n = 107) and 6-12 months (n = 166) of data, significant reductions were observed in annualized rates of exacerbations (62%; P < 0.001 and 65%; P < 0.001, respectively), with similar reductions in the rates of hospitalizations and emergency department visits. Benralizumab recipients with blood eosinophil counts (BEC) of ≥ 300/ µL and < 300/ µL at baseline and 12 months of data also had significant reductions in exacerbations (68%; P < 0.001, 61%; P < 0.001). CONCLUSION: This real-world, noninterventional analysis reinforces the clinical value of benralizumab in the management of patients with eosinophilic SA.

Albuterol-Budesonide Pressurized Metered Dose Inhaler in Patients With Mild-to-Moderate Asthma: Results of the DENALI Double-Blind Randomized Controlled Trial.

BACKGROUND: In the phase 3 MANDALA trial, as-needed albuterol-budesonide pressurized metered-dose inhaler significantly reduced severe exacerbation risk vs as-needed albuterol in patients with moderate-to-severe asthma receiving inhaled corticosteroid-containing maintenance therapy. This study (DENALI) was conducted to address the US Food and Drug Administration combination rule, which requires a combination product to demonstrate that each component contributes to its efficacy. RESEARCH QUESTION: Do both albuterol and budesonide contribute to the efficacy of the albuterol-budesonide combination pressurized metered-dose inhaler in patients with asthma? STUDY DESIGN AND METHODS: This phase 3 double-blind trial randomized patients aged ≥ 12 years with mild-to-moderate asthma 1:1:1:1:1 to four-times-daily albuterol-budesonide 180/160 µg or 180/80 µg, albuterol 180 µg, budesonide 160 µg, or placebo for 12 weeks. Dual-primary efficacy end points included change from baseline in FEV1 area under the curve from 0 to 6 h (FEV1 AUC0-6h) over 12 weeks (assessing albuterol effect) and trough FEV1 at week 12 (assessing budesonide effect). RESULTS: Of 1,001 patients randomized, 989 were ≥ 12 years old and evaluable for efficacy. Change from baseline in FEV1 AUC0-6h over 12 weeks was greater with albuterol-budesonide 180/160 µg vs budesonide 160 µg (least-squares mean [LSM] difference, 80.7 [95% CI, 28.4-132.9] mL; P = .003). Change in trough FEV1 at week 12 was greater with albuterol-budesonide 180/160 and 180/80 µg vs albuterol 180 µg (LSM difference, 132.8 [95% CI, 63.6-201.9] mL and 120.8 [95% CI, 51.5-190.1] mL, respectively; both P < .001). Day 1 time to onset and duration of bronchodilation with albuterol-budesonide were similar to those with albuterol. The albuterol-budesonide adverse event profile was similar to that of the monocomponents. INTERPRETATION: Both monocomponents contributed to albuterol-budesonide lung function efficacy. Albuterol-budesonide was well tolerated, even at regular, relatively high daily doses for 12 weeks, with no new safety findings, supporting its use as a novel rescue therapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT03847896; URL: www. CLINICALTRIALS: gov.

Number of patient-reported asthma triggers predicts uncontrolled disease among specialist-treated patients with severe asthma.

BACKGROUND: Patients with severe asthma (SA) experience a high disease burden, often precipitated by exposure to disease triggers. OBJECTIVE: To evaluate the prevalence and effects of patient-reported triggers on asthma disease burden in a cohort of subspecialist-treated patients with SA in the United States. METHODS: CHRONICLE is an observational study of adults with SA receiving biologics or maintenance systemic corticosteroids or whose disease is uncontrolled on high-dosage inhaled corticosteroids and additional controllers. Data were analyzed for patients enrolled between February 2018 and February 2021. This analysis evaluated patient-reported triggers from a 17-category survey and associations with multiple measures of disease burden. RESULTS: Among 2793 enrolled patients, 1434 (51%) completed the trigger questionnaire. The median trigger number per patient was 8 (interquartile range, 5-10). The most frequent triggers were weather or air changes, viral infections, seasonal allergies, perennial allergies, and exercise. Patients reporting more triggers experienced more poorly controlled disease, worse quality of life, and reduced work productivity. The annualized rates of exacerbations and asthma hospitalizations increased by 7% and 17%, respectively, for each additional trigger (both P < .001). For all measures, trigger number was a stronger predictor of disease burden than blood eosinophil count. CONCLUSION: Among US specialist-treated patients with SA, asthma trigger number was positively and significantly associated with greater uncontrolled disease burden across multiple measures, which highlights the importance of understanding patient-reported triggers in SA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03373045.

Relationship Between Asthma Control as Measured by the Asthma Impairment and Risk Questionnaire (AIRQ) and Patient Perception of Disease Status, Health-Related Quality of Life, and Treatment Adherence.

Purpose: Critical asthma outcomes highlighted in clinical guidelines include asthma-related quality of life, asthma exacerbations, and asthma control. An easy-to-implement measure of asthma control that assesses both symptom impairment and exacerbation risk and reflects the impact of asthma on patients' lives is lacking. Hence, the objective of this study was to assess the Asthma Impairment and Risk Questionnaire (AIRQ®) construct validity relative to patient self-perception of asthma status and validated disease-specific patient-reported outcome (PRO) measures. Patients and methods: Baseline data were analyzed from patients (aged ≥ 12 years) with asthma participating in a 12-month observational study assessing the ability of AIRQ to predict exacerbations. At entry, patients completed a sociodemographic questionnaire, AIRQ, 3 questions addressing self-perceived asthma status, Saint George's Respiratory Questionnaire (SGRQ), mini-Asthma Quality of Life Questionnaire (AQLQ), and Adult Asthma Adherence Questionnaire (AAAQ). Descriptive statistics were calculated for demographic and clinical characteristics. AIRQ construct validity was evaluated by assessing correlations between total AIRQ score and patient self-assessments, SGRQ, mini-AQLQ, and AAAQ scores. Comparisons of SGRQ, mini-AQLQ, and AAAQ total and component/domain scores by AIRQ control category were performed using general linear models and Scheffe's post hoc adjustments for pairwise comparisons. Results: A total of 1112 patients were enrolled: 70% female, 78% White, mean (standard deviation) age 43.9 (19.5) years. There were highly significant correlations between AIRQ score and patient self-perception of overall control (r = 0.69; p < 0.001), total SGRQ (r = 0.74, p < 0.001), and mini-AQLQ (r = -0.78, p < 0.001) scores. As AIRQ control category worsened, so did total and domain SGRQ, mini-AQLQ, and AAAQ impediment-to-inhaled-corticosteroid-adherence scores (all pairwise comparisons p < 0.001). Conclusion: Findings demonstrate the construct validity of AIRQ relative to patient self-perception of asthma status, disease-specific PRO measures, and treatment adherence barriers. AIRQ can be a useful instrument to raise awareness of the unrecognized impacts of asthma on patients' lives.

Dupilumab Efficacy in Patients With Uncontrolled or Oral Corticosteroid-Dependent Allergic and Nonallergic Asthma.

BACKGROUND: Type 2 cytokines IL-4/IL-5/IL-13 play an important role in pathogenesis of type 2 conditions, including asthma. Dupilumab, a human monoclonal antibody, blocks the shared receptor component for IL-4/IL-13, inhibiting signaling. In phase 2b (P2B) (NCT01854047) and phase 3 VENTURE (NCT02528214), dupilumab reduced annualized severe exacerbation rates (AER), improved forced expiratory volume in 1 second (FEV1), and was generally well tolerated in patients with uncontrolled, moderate-to-severe, or oral corticosteroid (OCS)-dependent severe asthma. OBJECTIVE: The post hoc assessment of dupilumab efficacy versus placebo in P2B and VENTURE in patients stratified by allergic status. METHODS: Allergic asthma was defined as total serum IgE ≥30 IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35 kU/L at baseline. AER, prebronchodilator (BD) FEV1, FEV1/forced vital capacity (FVC) ratio, asthma control (5-item Asthma Control Questionnaire), health-related quality of life (HRQoL; Asthma Quality of Life Questionnaire), type 2 biomarkers, specific IgE, and OCS reduction (VENTURE only) were assessed. RESULTS: In patients with allergic asthma, dupilumab (P2B: pooled 200/300 mg; VENTURE: 300 mg) every 2 weeks versus placebo reduced AER (P2B: -60%, P < .01; VENTURE: -72%, P < .001), and, in P2B, increased pre-BD FEV1 (P < .01) and FEV1/FVC (P < .05). In both studies, dupilumab significantly improved asthma control and HRQoL and reduced most type 2 biomarkers. Dupilumab significantly reduced OCS use in VENTURE. Similar benefits were observed in patients without evidence of allergic asthma. CONCLUSIONS: Dupilumab significantly reduced AER and improved lung function, asthma control, and HRQoL in patients with or without evidence of allergic asthma.

Identifying Patients for Self-Administration of Omalizumab.

Omalizumab, a recombinant anti-immunoglobulin E (IgE) monoclonal antibody, is indicated for moderate to severe allergic asthma, chronic spontaneous urticaria, and nasal polyps, and is approved for self-administration. However, specific guidance on identifying candidates with characteristics suitable for this type of administration is lacking. To help address this issue, this article provides practical considerations for the health care provider treating patients with omalizumab. We encourage health care providers to consider self-administration of omalizumab as an option for all appropriate, but not all, patients, and we recommend an individualized approach when considering self-administration of omalizumab.

Long-Term Use of Maintenance Systemic Corticosteroids is Associated with Multiple Adverse Conditions in a Large, Real-World Cohort of US Adults with Severe Asthma.

There is growing recognition of the adverse consequences of maintenance systemic corticosteroid (mSCS) therapy in severe asthma (SA). The objective of this study was to describe the prevalence of potential adverse effects of long-term mSCS therapy in adults with specialist-confirmed SA in the United States (US). CHRONICLE is an ongoing, noninterventional, observational study of US adults with SA treated by allergists/immunologists and pulmonologists. Once enrolled, patients' duration of mSCS therapy was reported by sites based on medical record review. For patients enrolled between February 2018 and February 2021, the prevalence of SCS-associated conditions was evaluated among those with no reported history of mSCS use, or mSCS use with < 2 years or ≥ 2 years cumulative duration. Prevalence and incidence estimates were adjusted for age and smoking history. Of 2793 patients enrolled, 311 and 231 had mSCS use for < 2 and ≥ 2 years, respectively. In adjusted analyses, adrenal insufficiency, pneumonia, type 2 diabetes, osteoporosis/osteopenia, congestive heart failure, coronary artery disease, hypertension, anxiety, and depression were statistically significantly associated with any mSCS use. By duration, mSCS use ≥ 2 years was associated with osteopenia/osteoporosis, coronary artery disease, adrenal insufficiency, and diabetes-related neuropathy; mSCS use < 2 years was associated with depression and osteopenia/osteoporosis, and diagnoses of depression, anxiety, and hypertension during the 12 months prior to enrollment. Overall, among patients with specialist-confirmed SA, mSCS use was associated with a high prevalence of multiple adverse conditions. Healthcare professionals should employ mSCS-sparing treatment strategies to avoid these negative consequences.

Biologic use and outcomes among adults with severe asthma treated by US subspecialists.

BACKGROUND: Multiple biologics are now available for severe asthma (SA) treatment and can improve outcomes for patients. However, few available data describe the real-world use and effectiveness of multiple approved biologics, including biologic switching, among subspecialists in the United States. OBJECTIVE: To evaluate biologic use and associated exacerbation outcomes in a large cohort of subspecialist-treated US adults with SA. METHODS: CHRONICLE is an ongoing, noninterventional study of subspecialist-treated US adults with SA receiving biologics, maintenance systemic corticosteroids, or those persistently uncontrolled by high-dose inhaled corticosteroids with additional controllers. For enrolled patients, sites report asthma exacerbations and medication use starting 12 months before enrollment. For patients enrolled between February 2018 and February 2021, biologic use and exacerbation outcomes before and after biologic initiation are described. RESULTS: Among 2793 enrolled patients, 66% (n = 1832) were receiving biologics. The most used biologic (> 1 biologic use per patient allowed) was omalizumab (47%), followed by benralizumab (27%), mepolizumab (26%), dupilumab (18%), and reslizumab (3%). Overall, 16% of patients had biologic switches, 13% had stops, and 89% had ongoing biologic use. Patients starting and switching biologics experienced a 58% (1.80 vs 0.76 per patient-year) and 49% (1.47 vs 0.75 per patient-year) reduction in exacerbations, respectively (both P < .001), with a numerically greater reduction observed among those starting non-anti-immunoglobulin E biologics compared with anti-immunoglobulin E. CONCLUSION: Real-world starting and switching of biologic therapies for SA were associated with meaningful reductions in exacerbations. With increasing biologic options available, individualized approaches to therapy may improve patient outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03373045.