measuring patient compliance in antihypertensive therapy—some methodological aspects

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Journal of Clinical and Hospital Pharmacy (1982) 7,43-51. MEASURING PATIENT COMPLIANCE IN ANTIHYPERTENSIVE THERAPY* - SOME METHODOLOGICAL ASPECTS Hannes Enlund Depanmem of Communuy Health/Bulrion of Social Pharmacy, Uniuerriry of Kuopio, Finland SUMMARY The usefulness of prescription refilling patterns in assessing compliance was studied retrospectively in 33 1 subjects receiving antihypertensive drugs during 1 and 2 year follow-up periods in 1976 and 1977. The compliance distribution was J-shaped for both periods. The number of compliant patients decreased slightly when the follow-up period increased from 1 to 2 years. An arbitrary cutoff point (07) yielded 34% noncompliers during the 2 year period. By interviewing patients, an additional 5% of noncompliers so-called early drop-outs, were identified among those who had filled no antihypertensive prescriptions during the 2 year period. The second follow-up year yielded little additional infor- mation. Reliability of the results obtained with prescription monitoring was also assessed by interviewing patients concerning eventual hospital stays and physicians' verbal orders that were not recorded on the prescriptions. These factors did not S e c t the overall compliance distribution, even though some patients might have been classified incorrectly because of them. In research settings and in daily practice prescription monitoring is a useful tool for assessing patient compliance. INTRODUCTION During the past three decades the number of compliance studies has increased almost exponentially, although a plateau has been reached during the last years (1). Despite these numerous studies, knowledge about compliance and factors associated with it are still rather inadequate and even contradictory. This is partly due to the complexity of the phenomenon, partly due to the methods and criteria used in these studies, and partly due to real differences in different places and settings. Analysis of biological fluids is commonly considered to be the most reliable method for assessing compliance (2), but sometimes both realism and generality are sacrificed in favour of precision, i.e. the measuring technology is on such a high level that the measurements cannot be made in everyday practice or so that the results cannot be generalized to the target population. The pill-count method, based on remaining amounts of medicine, usually 'A preliminary paper was presented at the Workshop of Clinical Pharmacy, Oslo, October 8-10,1980. Correspondence: H. Enfund, University of Kuopio, P.O. Box 138, SF-70101 Kuopio 10, Finalnd. 0143-3180/82/03o(Mo43 502.00 0 1982 Blackwell Sficntific Publications 43

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Journal of Clinical and Hospital Pharmacy (1982) 7,43-51.

MEASURING PATIENT COMPLIANCE IN ANTIHYPERTENSIVE THERAPY* - SOME METHODOLOGICAL ASPECTS

Hannes Enlund

Depanmem of Communuy Health/Bulrion of Social Pharmacy, Uniuerriry of Kuopio, Finland

SUMMARY

The usefulness of prescription refilling patterns in assessing compliance was studied retrospectively in 33 1 subjects receiving antihypertensive drugs during 1 and 2 year follow-up periods in 1976 and 1977. T h e compliance distribution was J-shaped for both periods. The number of compliant patients decreased slightly when the follow-up period increased from 1 to 2 years. An arbitrary cutoff point (07) yielded 34% noncompliers during the 2 year period. By interviewing patients, an additional 5% of noncompliers so-called early drop-outs, were identified among those who had filled no antihypertensive prescriptions during the 2 year period. The second follow-up year yielded little additional infor- mation. Reliability of the results obtained with prescription monitoring was also assessed by interviewing patients concerning eventual hospital stays and physicians' verbal orders that were not recorded on the prescriptions. These factors did not S e c t the overall compliance distribution, even though some patients might have been classified incorrectly because of them. In research settings and in daily practice prescription monitoring is a useful tool for assessing patient compliance.

I N T R O D U C T I O N

During the past three decades the number of compliance studies has increased almost exponentially, although a plateau has been reached during the last years (1). Despite these numerous studies, knowledge about compliance and factors associated with it are still rather inadequate and even contradictory. This is partly due to the complexity of the phenomenon, partly due to the methods and criteria used in these studies, and partly due to real differences in different places and settings.

Analysis of biological fluids is commonly considered to be the most reliable method for assessing compliance (2), but sometimes both realism and generality are sacrificed in favour of precision, i.e. the measuring technology is on such a high level that the measurements cannot be made in everyday practice or so that the results cannot be generalized to the target population. The pill-count method, based on remaining amounts of medicine, usually

'A preliminary paper was presented at the Workshop of Clinical Pharmacy, Oslo, October 8-10,1980.

Correspondence: H. Enfund, University of Kuopio, P.O. Box 138, SF-70101 Kuopio 10, Finalnd.

0143-3180/82/03o(Mo43 502.00 0 1982 Blackwell Sficntific Publications

43

44 H. Enlund

involves asking patients to bring their leftover drugs with them to the next clinic visit or making unannounced home visits to the patients. This might be realistic in a 10-day antibiotic trial, but the providers of care cannot realistically be expected to visit all patients several times during long-term treatment. This measurement method is affected by those who forget to take their medicine with them to the clinic (3). Different modifications based on the same principle such as counting the days between prescription refills (4), might be useful in long-term care, however. The third commonly used method usually considered to be the most unreliable one (2, 5) is the patient interview. With this method precision is sacrificed, but something is gained in generality and realism; it is the only method that can distinguish between noncomprehension and noncompliance. Even though it has been shown that patients overestimate their degree of compliance, there is some evidence that an interview provides sufficient information about most patients for whom noncompliance is most critical (6,7).

The degree of compliance is not a single event, but a cumulation of many pill-takings or neglects. Nor is it a static phenomenon, because the regimen varies, as does compliance for the same drug in different situations. Furthermore, compliance by the same person to different drugs, even at the same time, can vary (8, 9). T h e means of measurement should summarize this behaviour so that in chronic diseases it is not influenced by a few missed doses. Trial situations, where only one or two antihypertensives are used, rarely simulate the real situation. Patients with hypertension often have other chronic diseases and may also use other prescription or OTC drugs for acute diseases. A good balance between generality, realism and precision should be the goal of every measurement. Knowing that all methods have deficiencies, this kind of balance is best achieved by simultaneously using several methods for measuring the same thing.

The purpose of this study was to evaluate prescription refilling patterns as a method for measuring long-term compliance in hypertension.

SUBJECTS A N D M E T H O D S

Study population In 1972 a 6.6% random sample of the populauon aged 25-59 years in the counties of North

Karelia and Kuopio, Finland were examined for the baseline survey of a comprehensive cardiovascular control program - the North Karelia Project. Subjects with blood pressure 175 mmHg systolic and/or 100 mmHg diastolic or receiving antihypertensive drugs were classified as hypertensives. In 1977 this hypertensive cohort (now aged 3044 years) was re-examined in the terminal survey of the program. For assessing medication compliance, subjects living in the county capitals of Joensuu and Kuopio and nearby districts were included in this study. We excluded 32 subjects who had died during the 5 year period, ten subjects who had migrated and sixteen who could not be accurately identified during the different stages of the study or who had participated in any antihypertensive clinical trials. The final population for the study comprised 675 persons. Of these subjects, 570 participated in 1977 (84%). During 1976 and 1977, 331 had used antihypertensives. Details about drug use and compliance among nonparticipants has been presented in a previous paper (10).

Patient surveys The design of both the baseline and terminal surveys were strictly the same, except that in

1977 some additional information on antihypertensive therapy was included. The method

Measuring patient compl ia nee 45

used in the surveys was a combination of questionnaire, personal interview, and clinical assessment. In 1977, persons whose blood pressure reached 160 and/or 95 mmHg in two consecutive measurements or who were using antihypertensives were invited for a control visit within 2 weeks. Information on antihypertensive drug treatment was obtained both from the questionaire and from the drugs and prescriptions brought to the examination. Trade name, strength of the tablets, and daily dosage were recorded.

Prescnpn'on study

For assessing patient compliance, an indirect measuring method based on prescription refilling parterns was used. All prescription duplicates dispensed to the study subjects between June 1976 and June 1977 were examined retrospectively from the archives cf the Social Insurance Institution. Later the study period was extended by half a year at both ends, thus covering the years 1976 and 1977. About 96% of all prescriptions dispensed in the country are kept in these archives for 3 years after they are dispensed. In Finland prescribed antihypertensive drug treatment is provided free of charge for patients classified as chronic hypertensives. Costs are fully reimbursed to the pharmacy by the Social Insurance Institution. Thus, practically all antihypertensive drug prescriptions are included in this data bank. The prescription duplicates contain details of drug preparation, amount dispensed, dosage, indication given to the patient, and the dispensing dates. Information about free medication and whether the patient has had prescription medicine dispensed is also included. The amount of medication dispensed to a patient at one time may not exceed a 3-month supply. In practice, however, this rule does not work if the patient gets a new prescription from another physician. Although all antihypertensive medication records are available, they are not yet computerized. Thus, the data had to be collected manually and transferred to a computer for further analysis.

Calculations

Calculations of the degree of noncompliance were based on formulas presented elsewhere (8). The actual treatment period ( A ) for each drug was calculated from the difference between the first and last dispensing date and was compared with the theoretical treatment period (n during which the patient should have used his medicine if he followed instructions exactly. Thus, for each single drug used by the patient a compliance ratio (CR) was calculated; and for each patient a compliance score (CS) was determined taking into account compliance ratios for different drugs in the regimen according to length of the theoretical treatment period.

Obviously, the drug must be dispensed at least twice for a compliance ratio to be calculated. If the patient has, on an average, used his medicine as directed, the compliance score receives a value of 1; values less that this mean some degree of noncompliance, i.e. either too much or too little has been dispensed. Absolute values were necessary, otherwise a person taking too much of one drug and too little of another might receive a compliance score of 1.

46 H. Enlund

Intravariations between the different dispensing dates have not been taking into account. Thus, e.g., refilling 20 days too early at one time and 20 days too late at another will give a compliance score of 1, completely compliant. With poor compliance it is possible to get a minus score (see Fig. 1). Using differences between the theoretical and actual treatment periods for different drugs, the direction of the deviation was also analysed. An arbitrary division of good and poor compliance was made at compliance score 0.7.

The formula usually used in pill-counts (CR = taken amount/prescribed amount) was compared with that used in this study (Fig. 1). The relationship between the two formulas is CS= 2 - l /CR. Thus, a compliance score of 0.7 on our scale is equivalent to 0-77 on the other scale.

Fig. 1. Relationship between the valuer based on the compliance ratio (amount of drug taken/amount of drug prescribed) and compliance score used in this study.

RESULTS Compliance distribution

When using prescription refilling patterns as a measure of compliance, obviously the measured compliance approaches actual compliance as the follow-up period is lengthened. On the other hand, to save resources and perhaps to take some action toward altering poor compliance, a short period would be preferable. The compliance distribution with follow-up times of 1 and 2 years are seen in Fig. 2. The shapes of the distributions are similar, resembling a J for both periods. Using the rough classification of good and poor compliance, about 70% of patients were considered compliant and 30% noncompliant. There was a slight decrease in patients with very good compliance and an increase in those with very poor compliance when the length of the follow-up period increased. The difference is not great on a population level, but on the individual level there are some differences (Table 1).

Measuring patient compliance

30

g ,” 20 !?

a t 0

10

f .. Poor Good

p--- I - - -4 ..

. - - - I

L

---7

‘.

47

Table 1. Comparison of compliance classifications using follow-up periods of I and 2 years

Classified compliance Two years Total number

One year Good Poor of patients

Good 173 20 193 Poor 26 63 89

Total 199 83 282

Sensitivity 1731199 = 087. Specificity: 63/83 = 076. 173 + 63

282 Accuracy: - = 084.

Compliance scores for both follow-up periods were available for 282 patients. Using the figures for the 2-year follow-up period as standard, sensitivity (proportion of compliers correctly identified) was 87%; and specificity (proportion of noncompliers correctly identified) was 76% for the 1 year follow-up period. As the compliance score tells only the magnitude of deviation from given instructions, the direction of the deviations is presented in Table 2. Only 4% of the patients had filled all their prescriptions exactly according to given instructions (I). The 96% who deviated to any degree from instructions can be divided into three categories: 12% taking too many tablets (11), 59% taking too few tablets (IV), and 25% taking too much of one drug and too little of another. In the last category were somewhat more patients who had a net deviation in the negative direction (V) compared to those with a positive net deviation (111). Of the 193 patients with a compliance score of 3 0.7 (classified above as compliers), 72% had a negative deviation (i.e., taking somewhat less than prescribed); and 28% had a positive deviation. Figures for the 107 patients with poor compliances ( < 0 7) were 93% negative and 7% positive.

48 H. Enlund

Table 2. Antihypertensive drug taking behaviour: compliance scores calculated for the 2-year follow-up

Compliance score

Drug taking behaviour 1 0 - 0 9 0 8 9 - 0 8 0 7 9 - 0 7 0 6 9 - Total

I As prescribed 13 0 0 0 13 (4%) I1 Too many tablets 17 14 1 4 36 (12%) 111 Mixed ( + )* I 2 8 2 4 26 (8%) IV Too few tablets 34 30 36 84 184 (59%) V Mixed ( - ) * * 9 21 9 15 54 ( I 7%)

Total 85 13 48 107 313

taking too much of one drug and too little of another, net devlauon in a positive duecuon *. net deviation in a negauve duectlon

Reliability of the measuring method

The method used is based on at least two dispensing times. A methodologically interesting group are those patients who had only one prescription during the follow-up period. During the 1-year follow-up there were 28 such patients; four of those and an additional 14 persons belonged to this category after the second year (Table 3). There has usually been a pause in drug treatment, which also is seen as a poor calculated compliance during the 2-year follow-up. This may explain the fact that the number with very poor compliance increased somewhat during the 2-year follow-up. In the questionnaire four of 22 patients reported physicians orders as the reason for not taking the medicine, and one reported side effects. The remaining 17 patients probably are true noncompliers.

Verbal changes in dosage given by the physician without concomitant corrections on prescription sheets, are a main factor influencing reliability of prescription monitoring. In this group of subjects this factor seemed to be a minor problem, as only 18 patients with 20 drugs from a total of 416 drugs (5%) reported a discrepancy between the dosage appearing on the prescription sheet and the physician’s verbal orders. About half of those patients had a poor calculated compliance score. Another factor influencing the calculated compliance is hospital days. About 10% of the patients reported on the questionnaire that they had been in the hospital more than 7 days during the preceding year. However, no difference in good or poor compliance was found between the two groups.

Table 3. Analysh based on 2-year follow-up of patients who rehlled prescription only once during the I YCX follow-up

Number of Compliance 2 years

prescription only once patients Good Poor Possible reason for refilling

Pause in drug treatment Drug treatment started Drug treatment stopped Unknown (only one prescripuon

Total

during both follow-up periods)

13 1 12 6 2 4 5 2 3

- - 4

20 5 10

Measwing patient compliance 49 Among the 239 persons from the original sample who had no antihypertensive

prescriptions during the 2-year follow-up, 49 reported that they sometimes had been taking drugs for high blood pressure. They had not used any drugs for hypertension for 3 - 5 years. On the questionnaire these people mostly answered that the decision to stop treatment was made by the physician. There were, however, eight persons who answered that they do not like to use drugs if not absolutely necessary and five who answered that they simply had forgotten to renew their prescriptions. If the 13 persons are added to the noncompliant group, the proportion of noncompliers increases to nearly 40%.

DISCUSSION The benefits of drug treatment in severe hypertension were shown in the 1950’s (11, 12). Later in the 1960’s the benefits in moderate hypertension were shown by Veterans Administration studies (13, 14). Recently it has been shown that treatment of mild hyper- tension is ~ l s o beneficial (15, 16). Thus, these recent studies may further increase the number of people receiving these drugs. In addition, medication that is often life-long needs to be taken into special consideration. It is very important to assess the outcome of treatment and to identify the factors that contribute to poor treatment results. Patient compliance is only one factor influencing the outcome. The physician’s choice of therapy and prescribing habits must be evaluated as well as the health care system, and also the performance of other personnel, (e.g., nurses and pharmacists) involved in the care of the patient.

Methodological considerations of prescription monuoring

Methodology and criteria used in assessing compliance are crucial factors in determining the impact of noncompliance on the outcome of therapy. The value of all measurements depends on their reliability and validity. Simple and accurate methods are needed for idenufying noncompliant patients in hypertension treatment. One method is to use prescription refilling patterns as a measure of patients’ drug-taking behaviour. As with all other methods, the prescription-refilling method has its advantages and disadvantages. The measured parameter is not the actual drug intake but the regularity of refillings. If the prescription is filled, it is not known whether tablets are actually taken and taken only by the person who has filled the prescription. If, however, the prescriptions are not filled, we can be sure that the drug is not taken.

The method described in this report cannot evaluate variances in compliance occurring between dispensing dates (i.e., are the morning tablets taken in the evening? Are forgotten pill-takings replaced by a double dose next time? etc.). In long-term care of hypertension, however, these alterations in given instructions are generally of minor importance because concentration of the drug in the plasma is seldom a predictor for reduction of blood pressure (17). In addition, the reduction of blood pressure might last for days after medication has been discontinued. When using sufficiently long follow-up periods, the amount of drug dispensed can be assumed to equal the amount of drug consumed. This study indicates that in a system with 3 months’ reming intervals four dispensing dates are enough, to get an accurate picture of compliance. Additional information gathered during the second year was of minor importance. In another study (9) it was shown that five refills was enough, when the patients obtained a 30-day supply of the drugs at one time. In a study concerning compliance among elderly patients ( 18) the correlation between compliance assessed by prescription records and tablet counts was very high (rr = 068; P<O.OOl). The authors also estimated that poor

50 H. Enlund

compliance with an individual medicine could be predicted accurately in 66% of cases and by combining interview to prescription record inspection, the accuracy was as high as 86%.

Short hospital stays do not seem to affect compliance rates on a population level when using prescription refillings as a measure. The same conclusion is true for verbal orders given by the physician. On the other hand, there might be individual patients who are wrongly classified for the reasons given above. As the prescription method cannot distinguish between noncompliance and noncomprehension, an interview could be indicated to disentangle the reasons for noncompliance. For instance, in digoxin therapy it has been shown that the patients also have rational reasons for not taking the drugs (19). From the stand point of improving compliance, the noncomprehending subgroup, who either have not understood instructions or are not able to handle their medicines, can at least theoretically be helped with more accurate information, better information techniques, calendar packages, auxilliary dispensing boxes such as Dosett8, or by educating and instructing the people directly involved with the patients’ medication routines (home nurses, relatives, etc.).

One advantage of the prescription refill monitoring method is that it can be used without patients being aware of it. On the other hand, this could also be seen as a negative aspect of the method, because of an important issue in our increasingly computerized world: the privacy of the patient.

The importance of using inception cohorts has been stressed (20) for avoiding the loss of so-called early drop-outs in calculations of degree of compliance. In this retrospective study some early drop-outs may have been counted in the group of subjects with only one prescription. In addition, some early drop-outs were among those persons with no prescriptions dispensed at all during the 2-year follow-up. However, information about whether they neglected their treatment was based on their own statements in the questionnaire and on clinical examinations.

The prescnption method in daily practice

The use of prescription monitoring is feasible in countries where prescription information is stored centrally, using either manual or EDP-systems. However, if the system is not computerized it is laborious to perform ad hoc studies retrospectively. In countries where patient medication profiles are kept in the pharmacies this kind of activity might be made part of the daily routine. In countries with standardized prescription sheets, like Finland, practically every physician, pharmacist or nurse involved in the care of hypertensives is able to control compliance just by following the refilling dates on the original prescription. In Finland this is done partly as a routine by pharmacists, because of an agreement with the Social Insurance Institution to deliver drugs free of charge to patients classified as chronic hypertensives. Under this agreement, pharmacists are economically responsible for not delivering drugs to the patients too often, with a margin of 14 d. As seen in the results of this study overuse is not a problem. However, underuse seems to be a secondary problem for the pharmacists. This is strange, considering that it is profitable for the pharmacy to make sure that the patient refills his prescriptions as prescribed. Thus, we need a more active role by the pharmacists to ensure that the patient understands instructions and is able to handle his drugs.

C O N C L U S I O N The method described for prescription monitoring is a useful tool for assessing patient compliance both in research settings and in daily practice. In general, compliance studies are

Measuring patient compliance 51

important; but we should not get lost in the state of the art. T h e ultimate goal is a more rational and safer therapy for the patients. Increasing compliance, however, might not always be in accordance with this goal if other factors influencing the therapy are not evaluated simultaneously.

A C K N O W L E D G M E N T

This study was supported by the Yrjo Jahnsson Foundation.

REFERENCES

I . Haynes, R.B. (1979) Introducuon. In: Compliance in Health Care (eds R. B. Haynes, D. W. Taylor & D. L. Sacken), pp. 1-7. The Johns Hopkins University Press, Baltimore and London.

2. Gordis, L. (1979) Conceptual and methodologic problems in measuring patient compliance. In: Compliance in Health Care (eds R. B. Haynes, D W. Taylor & D. L. Sacken), pp. 2 3 4 5 . The Johns Hopkins University Press, Baltimore and London.

3. Fletcher, S.W., Pappius, E.M. & Harper, S.S. ( 1 979) Measurement of medication compliance in a clinical setting. Comparison of three methods in patients prescribed digoxin. Archives of lnrernal Medicine, 139, 635-638.

4. Porter, A.M.W. (1969) Drug dcfaulong in a general pracucc. Eruish MedicalJournal, i , 218-222. 5 . Gordis, L., Markowitz, M. 81 Lilienfeld, A.M. (1969) T h e inaccuracy of using interviews to esumate

patient reliability in taking medications at home. Medical Care, 7, 49-54. 6. Park, L.C. & Lipman, R.S. (1964) A comparison of patient dosage deviation reports with pill counts.

PsychopharmucoloFa, 6,29+302. 7. Rickels, K. & Briscoe, E. (1970, Assessment of dosage deviation in out-patient drug research. Journal o j

Clinical Pharmacolag)., 10, 153-160. 8. Turakka, H., Enlund, H. & Tuomilehto, J. (1979) Drug use and patient compliance in hypertension

therapy. In: Progress in Clinical Pharmucy (cds D. Schaaf & E. van der Kleijn), pp 53-60. Elscvier/Xorrh Holland Biomedical Press, Amsterdam, New York and Oxford.

9. Inui, T.S., Caner, W.B., Pecoraro, R.E., Pearlman, R.A. & Dohan, J.J. (1980) Variations in patient compliance with common long-term drugs. ibfedicd Care, 18,986993.

10. Enlund, H., Tuomilehto, J. & Turakka, H. (1981) Patient report validated against prescription records for measuring use and compliance with antihypertensive drugs. Acra medico scandinaoica, 209, 27 1-276.

I I . Dustan, H.P., Schneckloth, R.E., Corcoran, A.C. & Page, I.H. (1958) The effectlvencss of long-term treatment of malignant hypertension. Circulufion, 18,644-65 1.

12. Mohler, E.R. & Freis, E.D. (1960) Five-year survival of patients with malignant hypertension treated with antihypertensive agents. Amenian Hran Journal, 60,329-335.

13. Veterans Administration Cooperative Study Group on Antihypertensive Agents (1967) Effects of treatment on morbidity in hypertension. 1. Results in patients with diastolic blood pressures averaging I I 5 through 129 mmHg. 30urna.I ofthe Amencan Medical Association, 202,1028-1034.

14. Veterans Administration Cooperative Study Group on Antihypertensive Agents (1970) Effects of treatment on morbidity in hypertension. 11. Results in patients with diastolic blood pressure averaging 90 through 114 m H g . Journal ofthe AmericJn Medual Association, 213, 1143-1 152.

15. Hypertension Detection and Follow-up Program Cooperative Group (1979) Five-year findings of the hypertension detection and follow-up program. Journal of the American Medical Assocumon, 242,

16. The Australian Therapeutic Trial in Mild Hypertension (1980) Report by the Management CommiKCC. Lancer, i , 1261-1267.

17. Ismili, Z.H. ( 1979) Correlation of pharmacological effects with plasma-levels of antihypertensive drugs in man. Annual Review of Pharmacologv and T O X I C O ~ O ~ ~ , 19,2552.

18. Wandless, I., Mucklow, J.C., Smith, A., Prudham, D. (1979) Compliance with prescribed medicines: a study of elderly patients UI the community. Journal ofrhe Royal College of Genrrd Pracnnonrrs, 29,391-396.

19. Weinuaub, M., Au, W.Y.W. & Lasagna, L. (1973) Compliance as a determinant of serum digoxin concentration. Journal ofthe Amencan Medical Association, 224,48 1 4 3 5 .

20. Sacken, D.L. (1976) Priorities and methods for future research. In: Compl~ance wirh Therapeuric Repmem (eds D. L. Sacken & R. B. Haynes!, pp. 169-189. l h c Johns Hopkins University Press, Baltimore and London.

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