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T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e current concepts
Thomas G. Pickering, M.D., D.Phil., Daichi Shimbo, M.D., From the Behavioral Cardiovascular Health and Hypertension Program, Department In the past 30 years, the techniques for measuring blood pressure to determine whether a patient has hypertension have undergone a substantial of Medicine, Columbia Presbyterian Medi-cal Center (T.G.P., D.S.); and the Zena change. The bulk of our knowledge about the risks of hypertension and the and Michael A. Wiener Cardiovascular benefits of treating it is based on the traditional method of taking a small number of readings with the auscultatory technique in a medical setting. However, such measurements, which are of enormous value on a population basis, often provide a poor estimate of risk in an individual patient for reasons such as poor technique of Copyright 2006 Massachusetts Medical Society. the observer, the “white-coat” effect (the transient but variable elevation of blood pressure in a medical setting),1 and the inherent variability of blood pressure.2 Any clinical measurement of blood pressure may be regarded as a surrogate measure for the “true” blood pressure of the patient, which may be defined as the mean level over prolonged periods. Two techniques have been developed to improve the estimate of true blood pressure — ambulatory monitoring and home monitor-ing (or self-monitoring). We discuss only ambulatory monitoring in this review.
Ambulatory blood-pressure monitoring was first described more than 40 years ago.3 The currently available ambulatory monitors are fully automatic and can re-cord blood pressure for 24 hours or longer while patients go about their normal daily activities. Most monitors use the oscillometric technique. The monitors (Fig. 1) measure about 4 by 3 by 1 in. (10 by 8 by 3 cm) and weigh about 4 lb (2 kg). They can be worn on a belt or in a pouch and are connected to a sphygmomanometer cuff on the upper arm by a plastic tube. Subjects are asked to keep their arm still while the cuff is inflating and to avoid excessive physical exertion during monitoring.
The monitors are typically programmed to take readings every 15 to 30 minutes throughout the day and night. At the end of the recording period, the readings are downloaded into a computer. Standard protocols are used to evaluate the accuracy of the monitors, and approved devices are usually accurate to within 5 mm Hg of readings taken with a mercury sphygmomanometer.4 An up-to-date list of vali-dated monitors is available (www.dableducational.org). Some devices have been developed that can also record 24-hour electrocardiograms, but they have not been widely used.
Ambulatory blood-pressure monitoring can provide the following three types of information, which are of potential value in the clinical field (Table 1): an esti-mate of the true, or mean, blood-pressure level, the diurnal rhythm of blood pres-sure, and blood-pressure variability. Currently, clinical guidelines exist only for estimating true, or mean, blood-pressure levels.5-7 n engl j med 354;22 www.nejm.org june 1, 2006 Subjects with normotension have a pronounced diurnal rhythm of blood pressure.10 Blood pres-sure falls to its lowest level during the first few hours of sleep, and there is a marked surge in the morning hours coinciding with the transition from sleep to wakefulness. The average difference be-tween waking and sleeping systolic and diastolic pressure is 10 to 20 percent. Patients with hyper-tension usually have the same pattern, but the di-urnal profile of blood pressure is set at a higher level.10 In some subjects, whether they have normo-tension or hypertension, the normal nocturnal fall of blood pressure is diminished (<10 percent), Figure 1. Ambulatory Blood-Pressure Monitor.
and this is referred to as a nondipping pattern, in The sphygmomanometer cuff is connected to the 1st contrast to the normal dipping pattern. In extreme or by means of a tube that goes under the shirt.
cases (e.g., patients with autonomic insufficiency), the blood pressure rises during the night. The non- Blood-Pres
EMail sure Level
dipping pattern is common in blacks11 and has 16p6 y multiple causes, such as a high level of activity AUTHOR,-based
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the relationship is such that at low clinic blood- coids, and the presence of renal disease. Nondip-pressure 06-01-06 ping has been proposed as one reason why blacks higher, and at high clinic blood-pressure levels, are at higher risk for cardiovascular disease than
the ambulatory blood pressure is lower.8 The day- are members of other races or ethnic groups.
time level of ambulatory blood pressure that is
usually considered the upper limit of normal is Blood-Pressure Variability
135/85 mm Hg.6 This cutoff is reasonable because There are many different ways of measuring
it corresponds approximately to a clinic blood variability, ranging from beat-to-beat changes to
pressure of 140/90 mm Hg and, furthermore, it is changes over periods of weeks or months.12 Be-
the threshold above which cardiovascular risk cause the readings are taken intermittently, ambu-
appears to increase markedly.9
latory blood-pressure monitoring can yield only a crude estimate of the true variations of blood Diurnal Rhythm of Blood Pressure
pressure, other than the changes related to sleep Evaluation of the time course of blood pressure as compared with wakefulness. The clinical sig-over a 24-hour period can be achieved only with nificance of blood-pressure variability remains un-the use of ambulatory blood-pressure monitoring. certain.
Table 1. Blood-Pressure Patterns That Can Be Determined by Means of Ambulatory Blood-Pressure Monitoring
and Other Methods.
Ambulatory Blood-
Clinic Blood-Pressure Home Blood-Pressure
Variable
Pressure Monitoring
Monitoring
Monitoring
n engl j med 354;22 www.nejm.org june 1, 2006 T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e compared the predictive value of the daytime blood pressure with that of the nighttime pres-sure; some have shown no difference,17,21 al- One trial comparing ambulatory blood pressure though others have reported that the best pre-with conventional clinic blood pressure included diction of risk comes from the nighttime blood patients whose hypertension had been treated at pressure.20,22the time of the initial measurements.13 Most such A related method of analysis is to examine studies, however, have included patients whose dipping patterns. There is some evidence that hypertension was untreated at the time of the persons with a nondipping pattern are at higher initial measurements but was treated according risk than those with a dipping pattern16; in addi-to the clinic blood pressure during the follow-up tion, patients with an excessive morning surge period. The follow-up period ranged from two to of blood pressure may also be at increased risk.23 eight years, and the general finding has been that One study that used continuous intraarterial blood-ambulatory blood pressure predicts cardiovascu- pressure monitoring24 showed that blood-pressure lar events better than clinic blood pressure does.14-22 variability was an independent predictor of in-Most of the studies used some measure of the creased left ventricular mass seven years later, mean level of ambulatory blood pressure as the even after controlling for blood-pressure level. predictor variable, but it is uncertain which com- Another prospective study, which used noninva-ponent of the 24-hour blood-pressure profile gives sive monitoring, showed that increased blood-the best prediction of risk.
pressure variability during the day did not pre- The major candidates for predictors are shown dict cardiovascular events after controlling for in Figure 2. The most widely used has been the factors known to be associated with variability mean 24-hour blood pressure. Many studies have (e.g., age, blood-pressure level, and diabetes).25 Pressure
Figure 2. 24-Hour Blood-Pressure Tracing in a Patient with Hypertension.
The white zones indicate the normal ranges of systolic pressure (top) and diastolic pressure (bottom). Adapted
from the dabl 24-hour Ambulatory Blood Pressure Measurement reporting system, dabl Disease Management
Systems (Ireland) (www.dabl.ie).
AUTHOR, PLEASE NOTE:
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exist for determining whether blood-pressure vari- ability over a 24-hour period is greater than nor-mal among patients with labile hypertension.
In addition to the prediction of cardiovascular
risk, ambulatory blood-pressure monitoring, when Resistant Hypertension
used in conjunction with clinic blood-pressure An exaggerated white-coat effect may be suspect-
assessments, is of potential value in a variety of ed in some patients whose clinic blood pressure
other clinical conditions.26,27 Some of these con- remains high even though they are taking three
ditions are listed in Table 2.
or more antihypertensive drugs. Two prospective studies have shown that a subgroup of patients White-Coat Hypertension
with resistant hypertension according to clinic White-coat hypertension is the only indication for blood-pressure criteria have normal ambulatory
ambulatory blood-pressure monitoring that has blood pressure and a benign prognosis.33,34 How-
been approved for reimbursement by the Centers ever, these patients with apparently resistant hy-
for Medicaid and Medicare Services in the United pertension could probably be identified with the
States. Suspected white-coat hypertension is de- use of home monitoring.
fined as a clinic blood pressure of 140/90 mm Hg
or higher on at least three occasions, with at Masked Hypertension
least two sets of measurements of less than In the past few years, interest has increased in
140/90 mm Hg in nonclinic settings, plus the ab- the phenomenon of masked hypertension, defined
sence of target-organ damage. The diagnosis is im- as a normal clinic blood pressure and a high am-
portant because it is generally accepted that pa- bulatory blood pressure. This condition is the
tients with white-coat hypertension are at relatively reverse of white-coat hypertension. The clinic
low risk and are unlikely to benefit from antihy- blood pressure of patients with masked hyper-
pertensive-drug treatment. Several studies have tension may underestimate the risk of cardiovas-
shown that drug treatment of white-coat hyper- cular events. A study of patients with treated hy-
tension reduces the clinic blood pressure but has pertension showed that about one third of those
a negligible effect on the ambulatory blood pres- seen in a hypertension clinic had masked hyper-
sure, which by definition is normal.28 In addition, tension, and over a five-year follow-up period,
the only study to investigate the effects of treat- their relative risk of cardiovascular events was
ing white-coat hypertension on morbid events 2.28 as compared with the patients whose blood
found no significant benefit.29 Sustained hyper- pressure was adequately controlled according to
tension may develop in some patients with white- the criteria for both clinic blood pressure and
coat hypertension, and the risk of stroke may ambulatory blood pressure.34 Other studies have
increase after six years.30 Therefore, long-term shown that masked hypertension in patients with
follow-up with repeated ambulatory blood-pressure untreated hypertension and often in those with
monitoring or home monitoring is essential.
Table 2. Recommendations for the Use of Ambulatory Blood-Pressure
Labile Hypertension
Monitoring in Clinical Practice.*
Labile hypertension is something of a misnomer, Indication
because all hypertension is labile. However, ambu- latory blood-pressure monitoring may prove help-ful in some patients with a history of paroxysmal hypertension. Pheochromocytoma may be suspect- ed in some of these patients, but the hyperten- sion associated with this condition is not always labile.31 A much more common cause of labile hypertension is panic attacks, which have been * JNC 7 denotes the Seventh Report of the Joint National Committee on Preven-shown to be accompanied by surges in both blood tion, Detection, Evaluation, and Treatment of High Blood Pressure,26 and WHO-ISH the World Health Organization–International Society of Hypertension.27 pressure and heart rate.32 Currently, no norms n engl j med 354;22 www.nejm.org june 1, 2006 T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e undiagnosed hypertension is associated with an blood-pressure monitoring for assessing treat-increased rate of target-organ damage35 and an ment effects in clinical trials include the ability adverse prognosis.17 The prevalence of masked hy- to evaluate the duration of action of a drug and pertension in the general population could be as to analyze its effects on nighttime blood pres-high as 10 percent.36 As with white-coat hyper- sure, the need to enroll fewer patients, and better tension, masked hypertension may be suspected correlation of the results with clinical outcomes.41 on the basis of high blood-pressure measurements In contrast to their effects on clinic blood pres-taken at home, and one study has shown that sure, placebos have a negligible effect on ambu-masked hypertension diagnosed solely on the latory blood pressure.42basis of home recordings is associated with in- One goal of some trials that have compared the effects of various drugs on cardiovascular events has been to determine whether the effects Postural Hypotension
are independent of the effects of the drugs on Postural hypotension is not an uncommon find- blood pressure. Ambulatory blood-pressure mon-ing in older patients who become dizzy when itoring has often not been included in these stud-standing for long periods and who may also have ies, but in one instance when it was — the Heart syncopal episodes. The blood pressure of patients Outcomes Prevention Evaluation Study43 — the with postural hypotension is unusually labile and changes in blood pressure recorded by ambula-depends on their body position. When such pa- tory monitoring in a small substudy were very tients are supine, the blood pressure may be quite different from the changes reported by clinic high, particularly during the night.38 Treatment measurements, suggesting that the benefit derived with vasopressor drugs and antigravity stockings from ramipril may have been due to its blood-is a compromise between permitting the blood pressure–lowering effects.44pressure to go too low and making it go too high. Therefore, ambulatory blood-pressure monitor- ing is essential for evaluating optimal blood- Ambulatory blood-pressure monitoring is not widely used in clinical practice, mainly because to Antihypertensive Tr e atment the expenses are often not reimbursed by insur- ance companies. Medicare pays between $56 and Routine Clinical Practice
$122 per 24-hour recording session, depending on Ambulatory blood-pressure monitoring is not the geographic region, but only for suspected commonly used in routine clinical practice for white-coat hypertension (defined as a high clinic evaluating the response to antihypertensive treat- blood pressure, the absence of target-organ dam-ment, mainly because of the high cost and the age, and evidence of normal blood pressure out-inconvenience of performing multiple ambulatory side the clinic). White-coat hypertension does not blood-pressure recordings. However, changes in warrant antihypertensive-drug treatment, but pa-ambulatory blood pressure correlate more closely tients who receive this diagnosis undergo annual than do changes in clinic blood pressure with the ambulatory blood-pressure monitoring. Therefore, regression of left ventricular hypertrophy during it has been estimated that if all patients with antihypertensive treatment.39 newly diagnosed hypertension were to undergo ambulatory blood-pressure monitoring, fewer drug Clinical Trials
treatments at an annual cost of at least $300 Ambulatory blood-pressure monitoring is used would be necessary, resulting in a net reduction frequently in clinical trials of antihypertensive in the cost of managing hypertension.45drugs and, to a lesser extent, in nondrug treat- Most patients find the technique of ambula- ment for hypertension. The reduction in blood tory blood-pressure monitoring acceptable.46 It is pressure is almost always smaller with ambula- typically performed on a workday, when the blood tory blood pressure than with clinic blood pres- pressure is often higher than on days when the sure.40 The potential advantages of ambulatory patient stays at home.47 n engl j med 354;22 www.nejm.org june 1, 2006 measuring blood pressure, the diagnosis of white- coat hypertension by means of ambulatory blood-pressure monitoring may reduce health care costs. Ambulatory blood-pressure monitoring is current- Ambulatory blood-pressure monitoring is also ly used only in the minority of patients with hyper- invaluable for assessing antihypertensive treat-tension, but its use is gradually increasing. The ments and should be included in studies designed monitors are reliable, reasonably convenient to to compare the effects of various drugs.
wear, and generally accurate. Ambulatory moni- Nighttime blood pressure can be assessed only toring can be regarded as the gold standard for with ambulatory blood-pressure monitoring, and the prediction of risk related to blood pressure, evidence suggests that a failure of blood pres-since prognostic studies have shown that it pre- sure to decrease at night may be associated with dicts clinical outcome better than conventional an adverse prognosis. Also unresolved is the ex-blood-pressure measurements. Therefore, a good tent to which ambulatory blood-pressure moni-case can be made for using this technique in all toring can be supplanted by home monitoring, patients in whom hypertension has been newly which was not included in most of the studies diagnosed by means of clinic blood-pressure mea- documenting the superiority of ambulatory mon-surements. The role of ambulatory blood-pressure itoring over traditional clinic blood-pressure mea-monitoring for diagnosing masked hypertension surements.
is uncertain.
No potential conflict of interest relevant to this article was Although ambulatory monitoring is relatively reported.
expensive in comparison with other methods of References
1. Pickering TG, Gerin W, Schwartz AR. 8. Little P, Barnett J, Barnsley L, Marjo-
16. Ohkubo T, Hozawa A, Yamaguchi J,
What is the white-coat effect and how ram J, Fitzgerald-Barron A, Mant D. Com- et al. Prognostic significance of the noc- should it be measured? Blood Press Monit parison of agreement between different turnal decline in blood pressure in indi-2002;7:293-300.
measures of blood pressure in primary viduals with and without high 24-h blood 2. Armitage P, Rose GA. The variability care and daytime ambulatory blood pres-
pressure: the Ohasama study. J Hypertens of measurements of casual blood pressure. sure. BMJ 2002;325:254.
I. A laboratory study. Clin Sci 1966;30:325- 9. Verdecchia P. Prognostic value of am-
17. Bjorklund K, Lind L, Zethelius B, Berg-
bulatory blood pressure: current evidence lund L, Lithell H. Prognostic significance 3. Kain HK, Hinman AT, Sokolow M. and clinical implications. Hypertension of 24-h ambulatory blood pressure char-
Arterial blood pressure measurements 2000;35:844-51.
acteristics for cardiovascular morbidity in with a portable recorder in hypertensive 10. Pickering TG, Harshfield GA, Klein-
a population of elderly men. J Hypertens patients. I. Variability and correlation with ert HD, Blank S, Laragh JH. Blood pres- “casual” pressures. Circulation 1964;30: sure during normal daily activities, sleep, 18. Sega R, Facchetti R, Bombelli M, et al.
882-92.
and exercise: comparison of values in nor- 4. O’Brien E, Pickering T, Asmar R, et al. mal and hypertensive subjects. JAMA 1982; blood pressures compared with office
Working Group on Blood Pressure Moni-
blood pressure in the general population: 11. Profant J, Dimsdale JE. Race and diur-
tension International Protocol for valida- nal blood pressure patterns: a review and teriose Monitorate e Loro Associazioni tion of blood pressure measuring devices meta-analysis. Hypertension 1999;33:1099- in adults. Blood Press Monit 2002;7:3-17.
5. O’Brien E, Asmar R, Beilin L, et al. 12. Parati G, Valentini M. Prognostic rele-
19. Kario K, Shimada K, Schwartz JE,
vance of blood pressure variability. Hyper- Matsuo T, Hoshide S, Pickering TG. Silent mendations for conventional, ambulatory tension 2006;47:138-8.
and clinically overt stroke in older Japa- and home blood pressure measurement. 13. Clement DL, De Buyzere ML, De Bac-
quer DA, et al. Prognostic value of ambu- 6. Pickering TG, Hall JE, Appel LJ, et al. latory blood-pressure recordings in patients 2001;38:238-45.
Recommendations for blood pressure mea-
with treated hypertension. N Engl J Med 20. Staessen JA, Thijs L, Fagard R, et al.
surement in humans and experimental 2003;348:2407-15.
Predicting cardiovascular risk using con- animals. 1. Blood pressure measurement 14. Perloff D, Sokolow M, Cowan RM, ventional vs ambulatory blood pressure in
in humans: a statement for professionals Juster RP. Prognostic value of ambulatory older patients with systolic hypertension.
from the Subcommittee of Professional blood pressure measurements: further JAMA 1999;282:539-46.
and Public Education of the American analyses. J Hypertens Suppl 1989;7:S3-
21. Khattar RS, Senior R, Lahiri A. Cardio-
Heart Association Council on High Blood S10.
Pressure Research. Circulation 2005;111: 15. Verdecchia P, Porcellati C, Schillaci G, sustained mild hypertension: a 10-year
697-716.
et al. Ambulatory blood pressure: an inde- follow-up study. Circulation 1998;98:1892- 7. Myers MG, Tobe SW, McKay DW, Bolli pendent predictor of prognosis in essen-
P, Hemmelgarn BR, McAlister FA. New tial hypertension. Hypertension 1994;24: 22. Dolan E, Stanton A, Thijs L, et al. Su-
algorithm for the diagnosis of hyperten-
793-801. [Erratum, Hypertension 1995;25: periority of ambulatory over clinic blood sion. Am J Hypertens 2005;18:1369-74.
n engl j med 354;22 www.nejm.org june 1, 2006 T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e after removal of a phaeochromocytoma. 40. Mancia G, Parati G. Office compared
with ambulatory blood pressure in assess- 23. Kario K, Pickering TG, Umeda Y, et al. 32. Shear MK, Polan JJ, Harshfield GA, ing response to antihypertensive treat-
Morning surge in blood pressure as a pre-
et al. Ambulatory monitoring of blood ment: a meta-analysis. J Hypertens 2004; dictor of silent and clinical cerebrovascu- pressure and heart rate in panic patients. 22:435-45.
lar disease in elderly hypertensives: a pro- 41. White WB. Advances in ambulatory
spective study. Circulation 2003;107:1401-6.
33. Redon J, Campos C, Narciso ML, blood pressure monitoring for the evalua-
24. Frattola A, Parati G, Cuspidi C, Albini Rodicio JL, Pascual JM, Ruilope LM. Prog-
F, Mancia G. Prognostic value of 24-hour nostic value of ambulatory blood pressure search and practice. In: White WB, ed. blood pressure variability. J Hypertens 1993; monitoring in refractory hypertension: Blood pressure monitoring in cardiovas-11:1133-7.
a prospective study. Hypertension 1998;31: cular medicine and therapeutics. Totowa, 25. Verdecchia P, Borgioni C, Ciucci A, et 712-8.
al. Prognostic significance of blood pres- 34. Pierdomenico SD, Lapenna D, Bucci A, 42. Mancia G, Omboni S, Parati G, Ravo-
sure variability in essential hypertension. et al. Cardiovascular outcome in treated gli A, Villani A, Zanchetti A. Lack of pla-Blood Press Monit 1996;1:3-11.
hypertensive patients with responder, cebo effect on ambulatory blood pressure. 26. Chobanian AV, Bakris GL, Black HR, masked, false resistant, and true resistant Am J Hypertens 1995;8:311-5.
et al. The Seventh Report of the Joint Na-
hypertension. Am J Hypertens 2005;18: 43. Svensson P, de Faire U, Sleight P, Yu-
tional Committee on Prevention, Detection, 1422-8.
suf S, Ostergren J. Comparative effects of Evaluation, and Treatment of High Blood 35. Liu JE, Roman MJ, Pini R, Schwartz ramipril on ambulatory and office blood
Pressure: the JNC 7 report. JAMA 2003; JE, Pickering TG, Devereux RB. Cardiac pressures: a HOPE substudy. Hypertension
289:2560-72. [Erratum, JAMA 2003;290: and arterial target organ damage in adults 2001;38:E28-E32.
197.]
with elevated ambulatory and normal 44. The Heart Outcomes Prevention Eval-
27. 1999 World Health Organization–
office blood pressure. Ann Intern Med uation Study Investigators. Effects of an International Society of Hypertension 1999;131:564-72.
angiotensin-converting–enzyme inhibitor, 36. Pickering TG. Effects of stress and ramipril, on cardiovascular events in high-
tension. J Hypertens 1999;17:151-83.
behavorial interventions in hypertension: risk patients. N Engl J Med 2000;342:145- 28. Pickering TG, Levenstein M, Walms-
what is masked hypertension? J Clin Hyper- ley P. Differential effects of doxazosin on tens (Greenwich) 2003;5:171-4.
clinic and ambulatory pressure according 37. Bobrie G, Chatellier G, Genes N, et al. 45. Krakoff LR. Cost-effectiveness of am-
to age, gender, and presence of white coat Cardiovascular prognosis of “masked hy-
bulatory blood pressure: a reanalysis. Hy- hypertension: results of the HALT Study. pertension” detected by blood pressure pertension 2006;47:29-34.
Am J Hypertens 1994;7:848-52.
self-measurement in elderly treated hyper- 46. Ernst ME, Bergus GR. Favorable pa-
29. Fagard RH, Staessen JA, Thijs L, et al. tensive patients. JAMA 2004;291:1342-9.
tient acceptance of ambulatory blood pres- Response to antihypertensive therapy in 38. Mann S, Altman DG, Raftery EB, Ban-
sure monitoring in a primary care setting older patients with sustained and nonsus- nister R. Circadian variation of blood in the United States: a cross-sectional sur- tained systolic hypertension. Circulation pressure in autonomic failure. Circulation vey. BMC Fam Pract 2003;4:15.
2000;102:1139-44.
47. Pieper C, Warren K, Pickering TG.
30. Verdecchia P, Reboldi GP, Angeli F, 39. Mancia G, Zanchetti A, Agabiti-Rosei A comparison of ambulatory blood pres-
et al. Short- and long-term incidence of E, et al. Ambulatory blood pressure is su-
stroke in white-coat hypertension. Hyper- perior to clinic blood pressure in predict- ing treatment-induced regression of left 1993;11:177-83.
31. Littler WA, Honour AJ. Direct arterial ventricular hypertrophy. Circulation 1997; Copyright 2006 Massachusetts Medical Society.
pressure, heart rate, and electrocardio-
95:1464-70. [Erratum, Circulation 1997;96: gram in unrestricted patients before and 1065.] receive immediate notification when
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