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Corresponding author. Department of Nursing and Health Sciences, Faculty of Health and Social Sciences, University of South-Eastern Norway, Grønland 58, 3045, Drammen, Norway.
Institute of Health and Society, Department of Nursing Science, University of Oslo, Oslo, NorwayDepartment of Research and Development, Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway
Department of Respiratory Medicine, Oslo University Hospital, Oslo, NorwayInstitute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
Almost 65% were still in the “high” class after 12 months.
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High symptom burden in COPD is consistent over time.
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The patients' individual symptom experiences should be the primary focus of treatment.
Abstract
Purpose
This study aimed to examine reclassification rates among classes of chronic obstructive pulmonary disease (COPD) patients based on their distinct symptom experiences and to assess how these subgroups differed in symptom scores and health-related quality of life (HRQoL) outcomes over one year. Moreover, we wished to assess how these subgroups differed in demographic and clinical characteristics at 12 months.
Patients and methods
This is a follow-up study of 267 patients with moderate, severe, and very severe COPD. Based on their distinct symptom experiences using the Memorial Symptom Assessment Scale (MSAS), three subgroups (i.e., “high”, “intermediate”, and “low”) were identified at baseline. In the present study, transitions between the subgroups at three, six, nine, and 12 months were investigated and calculated as reclassification rates. Differences among the subgroups in symptom scores and HRQoL at each time point and demographic and clinical characteristics at 12 months were evaluated using analysis of variance with post hoc comparisons.
Results
Almost 65% were still in the “high” class after 12 months. At 12 months, pairwise comparisons for respiratory function measurements were not significantly different. Compared to the “intermediate” and “low” class, patients in the “high” class were more likely to be women and had significantly more comorbidities, reported a significantly higher number of symptoms at all time points, and worse HRQoL scores.
Conclusion
Our findings suggest that the pattern of a high symptom burden in COPD is consistent over time. The patients' individual symptom experiences should be the primary focus of treatment.
Although shortness of breath is the most common symptom, patients with chronic obstructive pulmonary disease (COPD) may experience a wide range of symptoms [
] and co-occurrence of cough, dry mouth, lack of energy, feeling nervous, difficulty sleeping, pain, worrying, and difficulty concentrating have been reported [
Understanding breathlessness: cross-sectional comparison of symptom burden and palliative care needs in chronic obstructive pulmonary disease and cancer.
]. Analyzing the co-occurrence of multiple symptoms using cluster analysis may facilitate the development of targeted interventions to relieve the patients' symptom burden [
Our research group has previously found that ≥40% of COPD patients reported having 14 physical and psychological symptoms simultaneously. Three subgroups of COPD patients reported either low, intermediate, or high symptom experiences [
]. However, due to varying instrument selection, the precise composition of these clusters is still uncertain, and there is a need to examine the stability of symptoms over time [
]. Four subgroups of symptoms were identified, including emotional problems, memory function decline, sleep alteration, and pain and unpleasant sensation. Notably, the study included two measurements with an interval of four weeks, which may not provide enough information on the stability of symptoms over longer periods.
Subgroups of patients with specific symptom experience patterns have been associated with defined clinical characteristics and lower health-related quality of life (HRQoL). Identifying such subgroups may indicate possible treatment opportunities [
Subgroup analysis of symptoms and their effect on functioning, exercise capacity, and physical activity in patients with severe chronic obstructive pulmonary disease.
In the current study we wished to ascertain whether the previous symptom-defined groups are stable over time and aimed to examine reclassification rates among these three latent classes of COPD based on the Memorial Symptom Assessment Scale (MSAS) [
Subgroup analysis of symptoms and their effect on functioning, exercise capacity, and physical activity in patients with severe chronic obstructive pulmonary disease.
]. We also aimed to assess how these subgroups differed in symptom scores and HRQoL outcomes at five different time points over 12 months. Moreover, we wished to assess how these subgroups differed in demographic and clinical characteristics at 12 months.
2. Material and methods
2.1 Design, population, and recruitment
This is a longitudinal study of COPD patients with distinct symptom experiences recruited from three outpatient clinics and one referral hospital in Norway. COPD patients who participated in the study, completed the MSAS related to their symptom experience at enrollment (baseline) and at three, six, nine, and 12 months after enrollment. The study procedures are described in detail elsewhere [
In brief, patients were included if they were ≥18 years of age; diagnosed with moderate, severe, or very severe COPD according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification of airflow limitation in COPD [
]; able to read and understand Norwegian; and with no cognitive impairments as assessed by the nurse during the process of enrollment. Patients were excluded if they were receiving ongoing treatment for pulmonary infection, COPD exacerbation, or cancer diagnosis at enrollment.
Only patients who gave informed consent participated in the study. The study was approved by the hospital's Data Protection Officer (Reference no.: 09/5580) and the Regional Committees for Medical and Health Research Ethics (Reference no.: S-09102a).
2.2 Instruments
2.2.1 Clinical characteristics at 12 months
Research nurses obtained information on body mass index (BMI), and smoking history at the different clinics. Comorbidities were evaluated through self-report. Patients completed information on comorbidities by using the Self-Administered Comorbidity Questionnaire (SCQ-19) [
], which includes 16 common medical conditions and three optional conditions. To obtain the total number of comorbidities, the 19 medical conditions were summed (range 0–19) [
Lung volumes and forced ventilatory flows. Report working party standardization of lung function tests, European community for steel and coal. Official statement of the European respiratory society.
]. Classification of severity of airflow limitation based on post-bronchodilator FEV1 in patients with FEV1/FVC <0.70 were defined as mild (FEV1 ≥80% predicted), moderate (FEV1 50%–79% predicted), severe (FEV1 30%–49% predicted), or very severe (FEV1 <30% predicted) COPD [
]. As supplementary measures, partial pressure of oxygen in the arterial blood (PaO2), number of acute exacerbations (i.e., number of prednisolone courses) during the last 12 months, the occurrence of chronic bronchitis (i.e., daily mucopurulent sputum over more than three months in at least two consecutive years), and presence of emphysema (i.e., based on the clinician's assumptions upon inclusion and chest configuration) were registered.
Exercise capacity: The 6-min walk test (6MWT) was used to measure exercise capacity. The 6MWT measures the exercise capacity with the distance walked to the closest meter. The 6MWT has shown satisfactory validity and reliability in studies including patients with COPD [
]. The mMRC is a 5-level rating scale from 0 (not troubled by breathlessness except during strenuous exercise) to 4 (too breathless to leave the house or breathless when dressing or undressing) that measures perceived disability based on the patients' perception of functional limitation with daily activities. The mMRC is a well-known scale in terms of assessing the patients' level of dyspnea [
2.2.2 Multiple symptoms at baseline, and 3, 6, 9 and 12 months
To measure multiple symptoms the MSAS was used. The MSAS consists of a list of 32 common symptoms that are used to assess the multiple dimensions of a patient's symptom experience during the past week [
]. Patients are asked to indicate whether they had each symptom (i.e., occurrence) and to rate its frequency, severity, and distress. In the current study, the occurrence dimension of MSAS, was used to identify and follow three subgroups of patients at enrollment (baseline), and time points three, six, nine, and 12 months. Based on the symptom occurrence rates of the fourteen most common symptoms from the MSAS, the three subgroups were named “high”, “intermediate”, and “low”. The symptoms were shortness of breath, lack of energy, feeling drowsy, dry mouth, cough, worrying, pain, feeling bloated, difficulty sleeping, feeling sad, problems with sexual interest or activity, feeling nervous, feeling irritable, and difficulty concentrating [
In addition, the MSAS total score and mean number of symptoms were calculated at the four time points. The three subscale scores; the psychological subscale (PSYCH), the physical subscale (PHYS), and the global distress index (GDI) were calculated at 12 months. The validity and reliability of the MSAS are well described in Portenoy's original work and have been used in several studies of COPD patients [
Symptoms and impact of symptoms on function and health in patients with chronic obstructive pulmonary disease and chronic heart failure in primary health care.
]. To our knowledge no sensitivity tests are performed.
2.2.3 Health-related quality of life at baseline, and 3, 6, 9 and 12 months
The St. George's Respiratory Questionnaire (SGRQ) was used to examine HRQoL at enrollment (baseline), and three, six, nine, and 12 months. The questionnaire has 50 items with 76 weighted responses to measure HRQoL in patients with respiratory disease. The SGRQ consists of three components (i.e., symptoms, activity, and impact) as well as the SGRQ total score [
]. Each of the component scores as well as the total score can range from 0 to 100. Higher scores indicate worse HRQoL, and a change of 4 in the total score is considered a clinically meaningful change [
The latent class analyses (LCA) were based on fourteen symptoms from the MSAS that occurred in ≥40% of the patients at baseline. The three subgroups (i.e., latent classes) of patients with distinct symptom experiences have previously been described [
]. The “high” class included high occurrence rates of both physical and psychological symptoms, while the “intermediate” class included higher rates of physical symptoms and lower rates of psychological symptoms, and finally, the “low” class included lower rates of both physical and psychological symptoms. In the current study, we employed LCA independently at each time point with an initial restriction to three classes. We monitored the fit of the models and allowed for a different number of classes if this led to a considerably better fit. Based on the fitted models we investigated transitions between the classes and specifically calculated reclassification rates based on the classification at baseline. The LCA were made in the GLLAMM package in Stata, version 16 [
Differences among the three subgroups in demographic and clinical characteristics at 12 months, and symptom scores and HRQoL for each time point (i.e., baseline, three, six, nine and 12 months) were evaluated using analysis of variance, Kruskal Wallis analyses, and chi-square analyses using IBM SPSS Statistics Version 26.0 (IBM Corp., Armonk, NY, USA). A p-value of <0.05 was considered statistically significant. Post hoc comparisons were made using the Bonferroni procedure.
3. Results
A total of 363 patients were asked to participate in the study. Sixteen patients did not meet the inclusion criteria and 55 declined to participate. Of the 292 patients enrolled, eight patients withdrew from the study and 17 patients did not return the questionnaires. The final sample consisted of 267 patients (response rate of 76.9%). Patients completed MSAS at baseline (n = 267), and at three (n = 233), six (n = 224), nine (n = 200), and 12 (n = 194) months after enrollment. No statistically significant differences were found at enrollment in age, gender, or number of comorbidities between patients who did and those who did not complete the questionnaire at 12 months. However, those who dropped out at 12 months had lower lung function at enrollment (baseline) than those who completed the study at 12 months.
3.1 Latent class analysis
A model with three latent classes fitted the data well for all time points, except for time-point six months where one of the groups became very small and a model with only two classes fitted the data considerably better. When assessing the patterns of the 14 symptoms used in the LCA at baseline, the probability of occurrence of each specific symptom seemed relatively constant across all time points. Based on the same assessment of occurrence probabilities, we considered the two fitted classes at six months to correspond to the “intermediate” and “high” class, respectively.
3.2 Reclassification rates from baseline and at 3, 6, 9, and 12 months
As shown in Table 1 and Fig. 1, for the patients who were classified with a “high” symptom burden at baseline, 64.7% were still in the “high” class at 12 months. For the patients who were classified as “low” at baseline, 81.8% were still “low” at 12 months, while none of them were reclassified as “high” (0.0%).
Table 1Reclassification rates from baseline to 3, 6, 9, and 12 months.
Class
Baseline
3 months
6 months
9 months
12 months
n = 267
n = 233
n = 224
n = 200
n = 194
L
I
H
L
I
H
L
I
H
L
I
H
Low
28 (10.5%)
50.0%
45.8%
4.2%
91.7%
8.3%
47.4%
42.1%
10.5%
81.8%
18.2%
0.0%
Intermediate
112 (41.9%)
32.7%
46.9%
20.4%
76.3%
23.7%
12.4%
65.2%
22.5%
37.9%
43.7%
18.4%
High
127 (47.6%)
5.4%
28.8%
65.8%
25.2%
74.8%
3.3%
28.3%
68.5%
10.6%
24.7%
64.7%
Notes: The table gives reclassification rates from baseline to the subsequent time points. Notice that the number of patients varies over the time course.
The Baseline column gives the distribution of the patients between the three classes at baseline. The remaining part of the table gives re-classification rates. As an example, among those who were classified as belonging to the “Low” class at baseline, 50% were still in “Low” after three months, while 45.8% of them were reclassified as belonging to the “Intermediate” class. In the same way, among those who were classified as “Low” at baseline, 81.8% were still “Low” after 12 months, while none of them were reclassified as “High”.
Finally, for the patients who were classified as intermediate at baseline, 76.3% were still in the “intermediate” class after six months while 43.7% were in the “intermediate” class at 12 months.
3.3 Differences in SGRQ and MSAS scores among the three subgroups at 3, 6, 9, and 12 months
As shown in Table 2, significant differences among the latent classes at three, six, nine and 12 months were found for the SGRQ symptom, activity, and impact scores as well as the total score. Significant differences were found in the expected direction at three, six, and nine months (i.e., “low” < “intermediate” < “high”). At 12 months, patients in the low class had significantly lower SGRQ symptoms, activity, impact, and total scores, compared to patients in the “intermediate” and “high” classes.
Table 2Differences in SGRQ and MSAS scores among the three latent classes at 3, 6, 9, and 12 months.
Note: At 6 months, the “low” class was not defined.
Abbreviations: HRQoL, Health Related Quality of Life; MSAS, Memorial Symptoms Assessment Scale; PHYS, physical; PSYCH, psychological; SD, standard deviation; SGRQ, St George Respiratory Questionnaire.
For the MSAS scores at 12 months, significant differences were found in the mean number of symptoms among the classes (i.e., “high” = 19.37 ± 5.37 > “intermediate” = 10.46 ± 3.41 > “low” = 4.92 ± 2.46). Significant differences among the classes in the GDI, PHYS, PSYCH subscale, and MSAS total score had the same pattern (i.e., “low” < “intermediate” < “high”).
3.4 Differences in patient characteristics among the subgroups at 12 months
Demographic and clinical characteristics at 12 months are presented in Table 3. The only respiratory measure that differed between the classes in the pairwise comparisons, was the mMRC dyspnea scale in the way that patients in the “high” and “intermediate” class reported significantly more functional dyspnea compared to patients in the “low” class.
Table 3Differences in demographic and clinical characteristics among the three latent classes after 12 months.
Understanding breathlessness: cross-sectional comparison of symptom burden and palliative care needs in chronic obstructive pulmonary disease and cancer.
Relative responsiveness of the chronic obstructive respiratory questionnaire, St Georges respiratory questionnaire and four other health related quality of life instruments with chronic lung disease.
Subgroup analysis of symptoms and their effect on functioning, exercise capacity, and physical activity in patients with severe chronic obstructive pulmonary disease.
Abbreviations: BMI, body mass index; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; kg, kilogram; kPa, kilopascal; m2, square meter; KW, Kruskal-Wallis test; mMRC, modified Medical Research Council Dyspnea Scale; PaO2, partial pressure of oxygen in blood; 6MWT, 6-min walk test; SD, standard deviation.
In pairwise comparisons, patients in the “high” class were more likely to be female compared with patients in the “low” and “intermediate” classes. Compared with the “low” and “intermediate” class, patients in the “high” class had a significantly higher number of comorbidities. When compared with the “low” class, patients in the “intermediate” class had significantly lower BMI.
3.5 Probability of occurrence of the 14 MSAS symptoms at baseline and 12 months
Probability of occurrence for the 14 MSAS symptoms in the three latent classes at baseline and 12 months is presented in Fig. 2. At 12 months, the most common symptom was shortness of breath with the highest probability of occurrence for all of the three classes. Lack of energy was the second most common symptom in the “intermediate” and the “high” classes.
Fig. 2Probability of occurrence for the 14 symptoms in the three latent classes at baseline and 12 months.
This study is the first to report reclassification rates in three latent classes of patients with COPD based on their distinct symptom experiences at 12 months. We found that 65% of the patients in the “high” class at baseline remained, and continually reported, a higher number of symptoms after 12 months. Regarding the patients in the “low” class, as many as 82% were still in the “low” class after 12 months, while none of these patients were reclassified as “high” (Table 1 and Fig. 1). Due to the relatively stable classes, the latent classes are presumed to capture the patients with the same symptom burden throughout time. Surprisingly, only two classes were found at six months (i.e., “high” and “intermediate”). We have no explanation for this, and seasonal variance is not a likely explanation since we included patients regardless of the seasons.
Furthermore, patients in the “high” class reported a probability of occurrence over 90% in several of the psychological symptoms, such as worrying, feeling sad, and feeling nervous (Fig. 2). At 12 months, these patients reported a significantly higher number of physical and psychological symptoms, varying from 19.15 ± 5.4 and up to 21.0 ± 5.6 compared to the “intermediate” and “low” classes (Table 2). Interestingly, a significantly higher fraction of the patients in the “high” class were women (66.2%) compared to the “low class” (Table 3). Conversely, in the “low class”, a significantly higher proportion were men. These patients were reporting a significantly lower number of symptoms, varying from 2.6 ± 2.2 and 5.4 ± 3.4, as well as fewer comorbidities, and less functional dyspnea (Table 2, Table 3). These findings may suggest that female patients with COPD consistently tend to report a higher symptom burden compared to men. Over the last decades, the prevalence of women diagnosed with COPD has increased along with the reporting of more severe COPD symptoms [
]. Taken together, these observations suggest that more attention should be given to symptoms in women with COPD.
The symptom with the highest probability of occurrence in all three classes at 12 months, was shortness of breath measured using MSAS. This finding is not surprising since airway obstruction is part of the definition of COPD, and shortness of breath is a highly rated and burdensome symptom known to increase among COPD patients with increasing stages of the disease [
]. In addition, research suggests COPD patients in a terminal stage of disease may experience a higher symptom burden compared to cancer patients, possibly because COPD patients often live longer with their disease burden [
]. Prolonged shortness of breath has previously been associated with symptoms such as fatigue, sleep disturbance, depression, anxiety, pain, and a higher number of comorbidities, as well as being a significant predictor of mortality in COPD [
The second most common symptom in the “intermediate” and the “high” classes were lack of energy, which may be related to fatigue. Linked to lack of energy is also feeling drowsy, and in the present study, the probability of occurrence of feeling drowsy was high in all three classes at 12 months compared to baseline [
]. Difficulty sleeping was rated considerably lower, which may suggest that the symptom of drowsiness may occur due to the total burden and the high number of symptoms.
Pain in COPD is a common and significant problem that needs attention. Although pain was not rated the most occurrent symptom, in both “high” and “intermediate” class the symptom of pain occurred in 79% and 62% of the patients, respectively (Fig. 2). In our baseline study, the probability of occurrence of pain in the “high” and “intermediate” class were 66% and 49% [
]. Research also shows that chronic pain is common in patients with COPD and that it has a negative impact on mood, breathlessness, interference with daily activities, and quality of life, and should be included in the management of the disease [
Interestingly, patients in the “low” class reported more physical symptoms that may be more known as respiratory- or COPD-related symptoms. In the ranking of symptoms cough and dry mouth were rated top three. While cough is regarded as one of the first symptoms in the manifestation of COPD [
], dry mouth may occur due to high doses of anticholinergic medications. As this symptom is associated with decreased nutritional intake and malnutrition, assessment of this symptom is crucial [
], no significant differences in pulmonary function were found between the classes at 12 months (Table 3). However, self-reported functional dyspnea using the mMRC dyspnea scale differed significantly among the classes at 12 months. Interestingly, the same pattern in pairwise comparisons among the three classes (“low” < “intermediate” and “high”) was found at baseline [
]. Moreover, the number of comorbidities differed significantly among the latent classes, and patients in the “high” class reported the highest number. Common comorbidities in our study are back and neck pain (47%), depression (26%), headache (24%), osteoarthritis (19%), and heart disease (18%), which could potentially explain the high symptom burden in this class. Consistent with findings from the present study, COPD patients often suffer from several comorbidities [
]. In terms of understanding the COPD patient's symptoms, research highlights the influence of various comorbidities that need to be taken into consideration when caring for these patients [
]. Finally, the patients in the “low” class had significantly higher BMI compared to the “intermediate” class, being slightly within the overweight range. Higher BMI or being overweight has been associated with a better prognosis in COPD and with a lower risk of exacerbations [
Further, patients in the “high” class reported significantly lower scores on all the subscales of SGRQ and total score of MSAS at all time points and all the subscales of the MSAS at 12 months compared to the other classes. These findings show how the burden of multiple co-occurring symptoms has a strong impact on HRQoL. In addition, comorbid conditions in COPD have been associated with worse HRQoL [
]. Results from the current study are consistent with previous research highlighting how patients with a higher symptom burden report significantly lower HRQoL and that the HRQoL is not necessarily dependent on specific clinical characteristics related to the diagnosis of COPD [
]. Individualized comprehensive symptom assessment is important to identify the patient's burden and to better meet their needs in coping with the disease.
In addition, we found significant decrements in HRQoL among all three classes at baseline and at 12 months. These findings suggest that the COPD patients' symptom burden is highly individual and not dependent of pulmonary function alone. Accordingly, research suggests that COPD patients experiencing dyspnea despite treatment may benefit from an even more specific treatment regarding their symptoms [
Some limitations need to be acknowledged. Although the MSAS includes 32 physical and psychological symptoms, COPD-related symptoms such as wheezing, chest pain, or chest pressure are not included in the list and could have contributed to more clarity in understanding the symptom experience of these patients [
]. However, using the original version of MSAS made us capable of comparing our results to other studies that also have used MSAS for measuring multiple symptoms.
Of the total number of patients included at baseline (n = 267), 46% had very severe COPD [
]. As these patients are only a minor part of the global COPD population, the classes identified in the current study may not generalize to all COPD patients. The patients who dropped out during the 12 months, had severe lung function (FEV1% predicted) at the time of inclusion, compared to the patients who completed the follow-up period. It is uncertain if these patients would have affected the analyses and distribution of classes. On the other hand, no significant differences were found at baseline in age, gender, or number of comorbidities between the patients who did and did not drop out of the study during the 12 months. Finally, due to insufficient data on medications at 12 months, we were not able to assess if the use of medications may have differed among the classes.
6. Conclusion
The reclassification rates along with the MSAS- and SGRQ scores as well as the patient characteristics in the current study, provide meaningful information about the stability in COPD patients' symptom experience and underlines the importance of a broad and individualized symptom assessment. Our findings suggest that the symptom burden in COPD patients continues over time. The subgroup with the highest burden of symptoms was associated with a higher number of female patients and patients with a higher number of comorbidities. Shortness of breath, which is a problematic and frequent symptom, was the overall highest rated symptom in all the three classes. Findings from our study emphasize the importance of considering the patients' individual symptom experiences which should be the primary focus in treatment.
Clinical implications
Multidimensional symptom assessments should be prioritized to better understand the patient's experience with the burden of disease and provide the specific treatment needed. Rehabilitation may be important to consider as it may help patients how to live with a higher symptom burden. Teaching patients when to contact medical help is of great importance and may also be a helpful strategy to better cope with the disease.
Future research
Interventional studies are needed to determine if different symptom management strategies may help to relieve multiple co-occurring symptoms.
Declaration of competing interest
The authors declare no competing interests. This study was funded by the South-Eastern Norway Regional Health Authority (2009055). Details reported at Clinical Trials: NCT01016587.
Acknowledgments
We are grateful to all the patients and clinicians who contributed to this study, especially the research nurses Gunilla Solbakk, Mari-Ann Øvreseth, and Britt Drægni.
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Understanding breathlessness: cross-sectional comparison of symptom burden and palliative care needs in chronic obstructive pulmonary disease and cancer.
Subgroup analysis of symptoms and their effect on functioning, exercise capacity, and physical activity in patients with severe chronic obstructive pulmonary disease.
Lung volumes and forced ventilatory flows. Report working party standardization of lung function tests, European community for steel and coal. Official statement of the European respiratory society.
Symptoms and impact of symptoms on function and health in patients with chronic obstructive pulmonary disease and chronic heart failure in primary health care.
Relative responsiveness of the chronic obstructive respiratory questionnaire, St Georges respiratory questionnaire and four other health related quality of life instruments with chronic lung disease.
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