American Journal of Respiratory and Critical Care Medicine

The test of single-breath diffusing capacity for carbon monoxide (Dl CO) has been widely used in population surveys. However, little is known about the effect of meeting or failing to meet the criteria for acceptability of this test. The American Thoracic Society (ATS) recommends a breathholding time of 9 to 11 s, two measurements within ± 10% or 3 ml CO(STPD)/min/mm Hg of the average Dl CO, and an inspiratory vital capacity (IVC) of at least 90% of the largest previously measured forced vital capacity (FVC) as criteria for this test. The objective of the present study was to examine the extent to which these criteria were met in a community study. To do this, a random sample of 3,740 persons, aged 15 to 70 yr, of the general population of the city of Bergen and 11 surrounding municipalities on the southwest coast of Norway were enrolled in a two-phase cross-sectional study. In the second phase, a stratified sample (n = 1,512) of the respondents to the postal questionnaire used for recruitment for the study (n = 3,370) were invited to a clinical and respiratory physiologic examination that included the Dl CO test. The attendance rate was 84% (1,275 of 1,512). In the examination, all subjects were able to maintain a breathholding time of 9 to 11 s, and 98% had two Dl CO values within ± 10% or 3 ml CO(STPD)/min/mm Hg of the average Dl CO. The criterion of an IVC of at least 90% of FVC in the two tests was met by 68% of the subjects. Younger age was an independent predictor of failure to meet the required criteria. Thus, only two-thirds of the participants fulfilled all of the ATS criteria for the Dl CO test, the main reason for failure being an IVC of less than 90% FVC. This should not necessarily lead to the exclusion from further analysis of those failing to meet this criterion.

The test for single-breath carbon monoxide diffusing capacity (Dl CO), also known as the transfer factor, is the most widely used noninvasive test of pulmonary gas exchange in respiratory medicine (1-4). The test has been applied in epidemiologic studies to assess predictors for impaired pulmonary gas diffusion (5-7). The American Thoracic Society (ATS) has since 1978 elaborated guidelines for standardization of Dl CO measurements and defined criteria for a successful test (3, 4, 8). The ATS recommendations include a breathholding time of 9 to 11 seconds, two technically acceptable measurements that agree within ± 10% or 3 ml CO(STPD)/min/mm Hg of the average Dl CO, and an inspiratory vital capacity (IVC) of at least 90% of the largest previously measured forced vital capacity (FVC).

Some of the previous epidemiologic studies of Dl CO were conducted before the ATS recommendations were published (6, 9, 10). To our knowledge, three studies (5, 7, 11) have followed the ATS guidelines. In the studies cited, the number of subjects meeting the criteria for a successful test varied from 50% (11) to 80% (7, 9), although in one study elsewhere (6) the success rate was not given. None but one of these studies characterized subjects who failed to meet the test criteria. Neas and Schwartz (5) observed that failure to provide an acceptable pulmonary diffusing capacity test was associated with advanced age, since 40% of the subjects in the age group of 65 to 74 yr in a national sample of adults in the United States had a missing Dl CO measurement, as compared with 22% in the age group of 20 to 54 yr. Whether the failure rate varies with sex, level of lung function, smoking habit, or educational level is unknown (5). Only one study has described the success rate for each of the three ATS criteria mentioned previously (11). Knudson and Burrows reported that in a general population of 1,421 subjects aged 7 yr and older, 11% had only one acceptable test, 3% did not succeed in meeting the breathholding duration of 9 to 11 s, and 2% did not have two diffusing capacity values that agreed within 10% or 3 ml CO(STPD)/min/ mm Hg. Further characteristics of these subjects are unknown.

The objective of the present study was to examine the extent to which the ATS criteria for the Dl CO test were met in a community study. We also wanted to examine the characteristics of those subjects not fulfilling the criteria for the test through demographic data, smoking habit, lung function, and educational level.

Subjects and Methods

The methods of selection and characteristics of the study population have been presented in detail elsewhere (12, 13). Briefly, the survey was a two-phase cross-sectional study. In the first phase, conducted in 1985, a questionnaire was mailed to a random sample of 3,740 persons, aged 15 to 70 yr, of the general population of the city of Bergen and 11 surrounding municipalities on the southwest coast of Norway. The response rate was 90% (12). In the second phase of the study, a stratified sample of subjects answering the questionnaire was invited to a clinical and respiratory physiologic examination in 1987 and 1988 (13). The stratification was based on information on smoking habit, occupational exposure, and respiratory symptoms, and on a physician's diagnosis of asthma or emphysema as obtained in the questionnaire phase (13). Altogether, 1,275 subjects presented for the second phase of the study, representing 84% of those invited (13). The study was approved by the Regional Ethical Committee of the University of Bergen.

Dl CO Measurements

The equipment used for measuring Dl CO has been previously described in detail (14). Measurements of Dl CO were made with a Gould 2100 automated system (SensorMedics BV, Bilthoven, The Netherlands), using a gas mixture that contained 10% helium, 0.3% carbon monoxide, 21% oxygen, and a balance of nitrogen. The breathholding time was preset to 10 s and the washout volume to 0.75 L. The sample bag (0.75 L) of the measurement system shuts off at a pressure of 13 cm H2O. The dead space of the sample bag was 6.25 ml (14). Each subject's height was measured in stocking feet to the nearest centimeter. Weight was measured without subjects wearing shoes, and with trousers with empty pockets. The subject was seated and fitted with a noseclip. Before the test was performed, each subject was instructed about all of the required maneuvers. A poster showing the different respiratory phases of the test was displaced in front of the subject. After the subject had adapted to the mouthpiece of the test apparatus, four or five tidal volumes were recorded to determine a regular end-expiratory baseline. The subject was then asked to exhale as far as possible, to the point at which he or she felt that the lungs had been totally emptied. This phase was encouraged but not coached by the laboratory technician. Other points that were emphasized included the importance of giving a sign when maximal exhalation had been reached (residual volume [RV]); making a rapid, maximal inhalation within 2 to 2.5 s to VC (coached by the technician); continuing to hold the breath for 10 s while relaxing against a closed glottis (assisted by the valve system); and exhaling rapidly (4, 14). The measurement itself was made only when the operator was certain that the subject had understood the procedure. Up to four maneuvers were performed to provide two error-free tests. A 4-min minimum interval was required between each test. If after four attempts an acceptable measurement could not be made, the procedure was abandoned.

The monitor screen of the test system displayed a dashed vertical time indicator and a dotted horizontal line at 0.95 of the subject's largest stored FVC. For each test, the duration of the breathholding time was displayed on the screen and controlled by the laboratory technician. When the breathholding time marked on the screen was achieved, the subject was instructed to exhale. The Jones and Meade method of determining the breathholding time, recommended internationally (1, 4, 15), was used in the study.

One trained laboratory technician conducted 96% of the Dl CO tests, and two chest physicians tested the remaining subjects (31 and 18 subjects, respectively).

The recommendation of obtaining two test results within 10% of the average Dl CO was not followed at the beginning of our study, since the study was begun before the ATS guidelines were published in 1987.

The helium and CO analyzers used in the study were calibrated with room air and the diffusion test gas. Gas concentration values were allowed to deviate by only ± 0.1% from one readout meter to another (14).

Spirometry was performed with the Gould 2100 spirometer. The inspiratory and expiratory limbs of the spirometer were calibrated automatically with a 2.1-L motor-driven syringe before each examination. The volume calibration was verified each day with a 3-L Gould Model M-20 calibrating syringe, with emptying times varying from 0.5 to 6 s (14). The variables recorded included FVC and FEV1. Three technically satisfactory measurements were obtained in which FVC was reproducible within 300 ml. A technically satisfactory test met the lung function testing criteria of the European Coal and Steel Community (16). The level of lung function was examined in terms of FEV1% predicted (17). The subject's FVC was defined as the maximal FVC, and was determined before the Dl CO test, as recommended by the ATS (4, 8).

Educational Level and Smoking Habits

Information about the educational level of subjects was obtained by asking the subjects to pick one of the following three alternative definitions of their schooling: (1) former primary school or present 9-year compulsory school; (2) continuation school, “folk high school” (people's college), Bible school, or the like, or lower secondary school, upper secondary school, or technical school; or (3) college or university. The three alternatives were respectively classified as primary, secondary, and university level (Table 1).

Table 1. CHARACTERISTICS OF A STRATIFIED SAMPLE OF A NORWEGIAN POPULATION BY SEX*

VariablesWomen (n = 571)Men (n = 596)
Age, mean (SD), yr 43 (16) 41 (16)
Smoking habit
 Nonsmokers, % 64 45
 Ex-smokers, % 12 23
 Current smokers, % 23 31
Educational level
 Primary, % 21 17
 Secondary, % 62 61
 University, % 17 21
Maximum FEV1, mean (SD), L  3.0 (0.7)  4.2 (0.9)
% FEV1, mean (SD), %  97 (15) 95 (15)
FEV1/FVC, mean (SD), % 81.8 (0.1) 81.3 (0.1)
Height, mean (SD), cm165 (6)178 (7)

*n = 1,167.

See text for explanation.

% FEV1 % predicted (17).

According to their smoking habits, subjects were divided into three groups: nonsmokers, ex-smokers, and current smokers. Nonsmokers were defined as subjects who had never smoked on a daily basis. Ex-smokers were those who had smoked on a daily basis but who had given up smoking prior to the survey. Smokers were those who smoked daily at the time of the study (18).

Statistical Analysis

Descriptive statistics were computed separately for women and men. Success rates in fulfilling the criteria for the Dl CO test were calculated separately in groups by age, smoking habit, educational level, and height, and were compared through the chi-square test. Unpaired t tests were used to compare mean values. Logistic regression analysis was applied to examine the relationship between success rates and possible predictors. Variables that were included in the analysis are listed in Table 3. Smoking habits and educational level were categorized according to the three groups mentioned earlier, and were analyzed according to the dummy-variable technique. All analyses were done with the BMDP statistical software package (University of California Press, Los Angeles, CA) (19).

Table 3. ADJUSTED ODDS RATIOS FOR FULFILLING THE CRITERION OF AN IVC/FVC RATIO  ⩾  90% IN TWO MEASUREMENTS ON A STRATIFIED SAMPLE OF A NORWEGIAN POPULATION WITH A MULTIPLE LOGISTIC REGRESSION MODEL INCLUDING ALL VARIABLES IN THE TABLE*

95% CI
VariableORLowerUpperp Value
Sex
 Women1NS
 Men0.910.601.38
Age, yr
 X1< 0.0001
 X + 101.431.271.60
Smoking habit
 Never smokers1NS
 Ex-smokers0.870.601.27
 Current smokers0.860.631.17
FEV1, L
 X1NS
 X + 10.80.621.04
Educational level
 Primary1NS
 Secondary0.980.671.44
 University1.100.691.74
Height, cm
 X1NS
 X + 101.200.901.55

Definition of abbreviations: CI = confidence interval; OR = odds ratio.

*n = 1,146.

See text for explanation.

Of the 1,275 attending subjects who presented for the second phase of the study, 108 were excluded because of a leak in the sample bag during the first 18 d of the study, leaving 1,167 subjects for inclusion in the analysis. Their basic characteristics are given in Table 1. Current smoking was more prevalent among men than among women. There were no sex differences with regard to mean age, educational level, or lung function in terms of % predicted FEV1. Of the 1,167 eligible subjects, 14 were not able to cooperate and hold their breath for 10 s, and two subjects could do so only for one test. Hence, 1.4% of the subjects were unable to fulfill the first of the ATS criteria. Of the 1,151 subjects who completed two tests, five were excluded because of unsatisfactory spirometric measurements of FVC performed before the Dl CO maneuver, leaving 1,146 subjects for further analysis. Of these, 1,121 (98%) subjects provided measurements within 10% or 3 ml CO(STPD)/ min/mm Hg of the average Dl CO (Table 2). The percentage of subjects meeting this reproducibility criterion did not vary by sex, age, smoking habit, or educational level (Table 2).

Table 2. PERCENTAGE OF SUBJECTS ACHIEVING TWO ACCEPTABLE TESTS WITHIN 10% OR 3 ml CO(STPD)/min/mm Hg OF AVERAGE Dl CO, IVC  ⩾  0.90 WITH MAXIMUM FVC AT BOTH MEASUREMENTS, AND BOTH CRITERIA BY SEX, AGE, SMOKING HABITS AND EDUCATIONAL LEVEL IN A STRATIFIED SAMPLE OF A NORWEGIAN POPULATION*

nTwo Tests Within 10% of Average Dl CO(%)IVC/FVC ⩾ 0.90 at Both Measurements (%)Both Criteria (%)
Sex
 Women555 987170
 Men591 986665
Age, yr
 18–34438 985555
 35–54399 977069
 55–73309 988583
Smoking habit
 Never smokers622 986867
 Ex-smokers208 987372
 Current smokers316 986565
Educational level
 Primary212 987574
 Secondary710 986666
 University224 976766
Height, cm
 < 160126 997575
 160–169401 987272
 170–179404 976664
 180–189190 996161
 ⩾ 190 251006464

*n = 1,146. Sixteen subjects were excluded because they could not perform two Dl CO measurements, and five additional subjects were excluded because they could not perform a satisfactory expiratory maneuver.

See text for explanation.

The criterion of an IVC of at least 90% of FVC in the two tests was met by 68% of the subjects who were able to perform two tests when the technician was the operator, and by 67% and 61%, respectively, of the subjects who performed two tests when the two chest physicians made the measurements. An IVC of at least 90% of FVC was met in only one transfer factor test by an additional 15% of the subjects. The mean ages of the group that met the criterion were 44 yr for men and 45 yr for women, versus 34 yr for men and 37 yr in women in the group that failed to meet the criterion (p < 0.01). As age increased (Table 2), the frequency of twice obtaining an IVC of at least 90% of maximum FVC increased from 55% to 85% (p < 0.0005, chi-square test). Sex, smoking habits, and educational level did not affect this frequency. A significant linear decrease in the proportion of subjects meeting the criterion of an IVC of at least 90% of FVC as a function of body height was found in both sexes (test for linear trend p = 0.001) (Table 2). The percentage of subjects meeting the criterion decreased from 76% for those with an FEV1 of 1 to 2 L to 45% for those with an FEV1 greater than 6 L (p < 0.0005). For both sexes, mean FEV1 in liters was greater in the group that failed to meet the criterion (men: 4.5 L/s; women: 3.1 L/s) than in the group that succeeded (men: 4 L/s; women: 2.9 L/s). Meeting the criterion was not correlated with the level of FEV1 in % predicted (p = 0.51).

Younger age was a significant risk factor for failure to achieve an IVC/FVC ratio ⩾ 0.90 in the two Dl CO measurements after adjusting for sex, smoking, educational level, height, and FEV1 in a logistic regression analysis (Table 3). None of the other variables entered into the multivariate analyses was significantly associated with the ability to achieve an IVC/FVC ratio ⩾ 0.90.

Figure 1 shows the distribution of the IVC/FVC ratio by sex and age for the study subjects. For simplicity, one test per subject is presented, taking the ratio of each subject's maximum IVC to the same subject's maximum FVC. Very few of the subjects failed to have an IVC/FVC ratio > 0.70. Among those failing to meet the criterion of an IVC/FVC ratio ⩾ 0.90, a percentage in men than of women had an IVC/FVC ratio of 0.70 to 0.79.

Table 4 shows the level of Dl CO by level of the IVC/FVC ratio. In an analysis of covariance, a significant interaction was found between the IVC/FVC ratio and sex (p < 0.0001). Separate analyses for men and women showed a significant negative trend in Dl CO with increasing IVC/FVC ratio for men (regression coefficient = −2.11, p < 0.01) and a positive trend for women (regression coefficient = +1.79, p < 0.01). Interaction between the IVC/FVC ratio and age was not significant (p = 0.61).

Table 4. COMPARISON OF Dl CO (mM/min/kPa) IN SUBJECTS AGED 18–73 yr BY MAXIMUM IVC/MAXIMUM FVC IN A STRATIFIED SAMPLE OF A NORWEGIAN POPULATION*

IVC/FVC < 0.80 0.80 ⩽ IVC/FVC < 0.90 IVC/FVC ⩾ 0.90 p Value for Interaction
nDl CO (SE)nDl CO (SE)nDl CO (SE)
Sex
 Men6110.95 (0.21)4610.06 (0.23)4849.77 (0.09)< 0.0001
 Women18 8.48 (0.33)54 8.66 (0.20)4838.86 (0.10)
Age§
 18–344910.50 (0.22)45 9.95 (0.21)3449.76 (0.09)
 35–542410.41 (0.30)42 9.33 (0.22)3339.31 (0.08)0.61
 55–73 6 8.98 (0.58)13 8.58 (0.42)2908.73 (0.11)

*n = 1,146.

IVC/FVC = maximum IVC/maximum FVC, with maximum IVC being the highest IVC value in the two Dl CO recordings.

Adjusted for age, height, and FEV1.

§Adjusted for sex, height, and FEV1.

The main findings of this general population study were that: (1) 67% of the participants fulfilled the three criteria for a successful Dl CO measurement; (2) a majority of those who failed to fulfill the criteria did so because they were unable to achieve an IVC/FVC ratio of 0.90 or greater for the two measurements, and a small proportion of subjects failed to cooperate in undergoing the test, including failing to meet the 10 s breathholding time or the reproducibility criterion; and (3) younger age was an independent predictor of failure to meet the required criteria.

The reproducibility criterion was defined after the study had been conducted, whereas the two other criteria were defined before it began. Hence, the results based on the former criterion should be interpreted cautiously. On the other hand, if this criterion had been set a priori, the percentage of subjects meeting it would probably have been even higher than the 98% observed.

The findings for the study participants should be representative of the general population surveyed, since the attendees did not differ significantly from the nonattendees in terms of demographic data, smoking habit, or prevalence of a physician's diagnosis of asthma or emphysema (13). The second-phase respondents were 5 yr older than those who did not respond. However, a response rate of 100% would have changed the mean age of the respondents only from 42 to 41 yr (13). Adjustment for the stratification did not alter the main conclusions in the study as described previously.

Our finding that about two-thirds of the study population met the ATS criteria for a successful Dl CO measurement is in crude agreement with that in previous population studies achieving success rates of from 50% to 80% (5, 7, 9). Failure rates varying from 20% to 50% in a Dl CO test are unacceptably high, especially when compared with a failure rate of about 12% when spirometric measurements are applied to general population samples (20). The high failure rates in the Dl CO test have been ascribed the complexity of the test as compared with spirometric measurements (8). However, our study showed that only a minor proportion of subjects failed the Dl CO test because of lack of cooperation or because of poor reproducibility of the recorded results.

Theoretically, there could be several explanations for our finding that a large proportion of our subjects failed to inspire from their residual capacity to within 90% of their FVC.

First, there could have been discrepancies in the measurements of FVC and IVC. Both FVC and IVC were converted to the same body temperature–ambient pressure–saturation (BTPS) conditions. In our study the expiratory and inspiratory variables were measured with the same type of mass flowmeter (two identical, unidirectional, heated-wire anemometers). The two instruments' performances were judged to be acceptable in dynamic waveform testing (21). During the data sampling, the two anemometers were calibrated twice daily and in tandem for both static and dynamic volumes, and no differences between the two devices were observed (14). Before each Dl CO maneuver, the inspiratory flow sensor was zeroed with diffusion test gas and the expiratory flow sensor was zeroed with room air. In the system used in our study, the helium content of the inspired gas was taken into account, using the flow sensor calibration as a correction factor.

Second, some subjects may have ended their inspiration in the Dl CO measurement prematurely because of a feeling of breathlessness caused by the resistance in the inlet circuit. If this resistance is too high, or if the subject has a high central airway resistance, a rapid inspiratory maneuver may effectively be a Muller maneuver (3). The Epidemiology and Standardization Project (EPS) recommends that the inspiratory and expiratory circuits used in Dl CO testing have a resistance of less than 1.5 cm H2O/L/s at a flow rate of 6 L/s, so that the inspiratory and expiratory phases of the test are not impeded (8). In the instrument we used, the resistance of the valve was less than 1.5 cm H2O/ L/ s at 12 L/s, thus falling well within the foregoing recommended limit.

Third, Leith and Mead (22) have suggested that the mechanism through which residual volume is measured differs in old persons and younger ones. During the forced expiration maneuver, the mechanism setting the lower limit to lung volume in young subjects is a static balance between the respiratory muscle forces and the elastic recoil forces occurring in the chest wall. In older subjects, the limiting mechanism operates in the lung and not in the chest wall. By producing very low maximum flows at low lung volumes, older subjects can prolong their expiratory effort until they reach the point of zero flow, which establishes the RV (22). When applying external pressures that assisted expiration at near RV, Leith and coworkers observed a decrement in lung volume only for younger individuals (22).

The expiratory spirometric maneuver, which yields the FVC value, is customarily coached vigorously by the attending technician and is preceded by a deep inspiration (23). The expiration prior to inhalation in the measurement of Dl CO is slower and is initiated at tidal volume (Vt), according to the ATS recommendations (4). This difference may cause the latter expiration to end at a higher RV than that for the expiration in spirometry. The subsequent inhalation in the measurement of Dl CO starts at a greater lung volume. Consequently, although a level of maximum inhalation is reached, the recorded IVC is less than the actual IVC, reducing the observed IVC/FVC ratio. Moreover, younger subjects may be more likely to achieve a lower RV during a forced expiration than during a slow one. This could explain our finding that fewer younger than older subjects met the criterion of an IVC/FVC ratio ⩾ 0.90.

Furthermore, the high failure rate in the IVC maneuver in our study could theoretically have been idiosyncratic to the technician conducting the tests. However, this failure rate did not differ significantly from that of the two chest physicians who also conducted Dl CO tests.

The age trend observed in the present study ran counter to that observed in a recently reported study of determinants of Dl CO involving 6,830 black and white Americans aged 25 to 74 yr (5). This study found an increasing rate of test failure with increasing age, although it was not stated which of the criteria defined for a successful test was not met. One explanation for the difference could be that the American study was restricted to subjects without lung disease, whereas our study covered an entire regional population. However, even after we excluded subjects with bronchial asthma and chronic obstructive lung disease from our analysis, the decrease in the Dl CO test failure rate with increasing age persisted.

We observed no difference in measured Dl CO between those subjects who failed to meet the criterion of an IVC/FVC ratio ⩾ 0.90 and those who did not. However, when men and women were analyzed separately, the observed Dl CO for men who failed to meet the criterion was significantly lower than that for men who met it (Table 4), whereas for women the opposite observation was made. This might indicate that there are partly different explanations for men and women for not reaching an IVC/FVC ratio ⩾ 0.90. Our observation for women agrees with that of a previous study (24). The observed value of Dl CO decreases with the level of inspiration at which the measurement is made. Hence, a higher proportion of women than of men may fail to reach their TLC during the inspiratory maneuver in the Dl CO measurement. A higher proportion of men than of women may start their inspiration at a level above their RV and reach their TLC even though their observed IVC/FVC ratio is below 0.90.

In previous community studies of Dl CO, subjects who failed to meet the criteria for a successful test have been excluded from further analyses (5, 6, 11, 25). Because the excluded subjects have represented large proportions of the population samples examined, their exclusion may significantly reduce the power of statistical tests. Furthermore, if the success rates in Dl CO measurement vary according to certain subject characteristics, the exclusion of subjects may introduce a bias into subsequent analyses. For instance, in both the study by Neas and colleagues (5) and in the present study the success rate varied by age. Theoretically, excluding subjects who fail to meet the Dl CO test criteria may bias any comparison of the diffusing capacity with an age-dependent variable.

Consequently, we would advocate that the reason for any failure in the Dl CO test should be noted. If the Dl CO measurement is technically satisfactory but the criterion of an IVC/ FVC ratio ⩾ 0.90 is not met, the subject should not necessarily be excluded from data analyses. Rather, separate analyses should be done of subjects meeting and those failing to meet the criterion. Alternatively, one could enter an adjustment into the analyses in terms of each subject's IVC/FVC ratio. Assessment should then be made of the magnitude of the potential error involved (3, 4).

In conclusion, the study we conducted showed that 67% of a general population sample fulfilled the ATS criteria for a successful Dl CO measurement. The majority of subjects who failed to meet the criteria did so because they were unable to achieve an IVC/FVC ratio of 0.90 or greater. The failure rate increased with younger age. These subjects should not necessarily be excluded from further analyses.

The authors would like to express their sincere thanks to Dr. John Cotes for his comments on the manuscript.

Supported by the Royal Norwegian Council for Scientific and Industrial Research, the Norwegian Research Council for Science and the Humanities, and the Norwegian Asthma and Allergy Association.

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Correspondence and requests for reprints should be addressed to Ida Welle, Department of Thoracic Medicine, Haukeland Hospital, University of Bergen, N-5021 Bergen, Norway. E-mail:

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