Letters
poured cold water over the idea that resveratrol as a dietary constituent prevents heart disease or cancer or prolongs life. The study suggests that the intake of red wine by elderly persons, as judged by urinary levels of resveratrol metabolites, did not affect overall mortality, incidence of cardiovascular disease or cancer, or biomarkers of incipient inflammation. This publication elicited considerable negative resonances in the international lay press (eg, “Red wine health benefits ‘overhyped’”).2 We submit that several aspects render the study unsuitable to warrant such negative resonance. Participants were classified into quartiles based on their urinary resveratrol metabolite levels measured once at the start of the study. We seriously doubt that this single value can accurately reflect lifetime exposure because the impact of resveratrol on health is likely to have been heavily influenced by consumption patterns prior to the investigation. The dose-response relationships that govern the efficacy of resveratrol are unclear and may display hormetic properties with opposing effects observed at small and large doses.3 In the study by Semba et al,1 the first quartile of urine levels contained values from participants who refrained from resveratrol consumption and those whose resveratrol intake was low, militating against the ability to tease out potential differences between resveratrol-naive participants and those with a low intake. Nutritional status of study participants is one of the many variables that affect disease prevention outcomes. Resveratrol is likely to engage its effects via subtle disturbances of abnormal cell metabolic processes associated with high fat intake typical of the Western diet.4 This means that resveratrol may cause its preventive efficacy only in individuals who have consistently ingested high amounts of fat and/or have the metabolic syndrome, but not in healthy ones.5 The article by Semba et al1 does not give any indication as to the amount of fat consumption by the participants. A quarter to a third of them were prediabetic or diabetic; assessment of study end points vs resveratrol consumption in this subgroup vis à vis the metabolically uncompromised participants might have been revealing. We believe that many more trials focusing on individuals characterized by a particular biochemical or pathological constitution or nutritional intake need to be performed before resveratrol can confidently be thrown out with the proverbial bath water. Karen Brown, PhD Alessandro Rufini, PhD Andreas Gescher, DSc Author Affiliations: Cancer Biomarkers and Prevention Group, Department of Cancer Studies, University of Leicester, Leicester, England. Corresponding Author: Andreas Gescher, DSc, Cancer Biomarkers and Prevention Group, Department of Cancer Studies, University of Leicester, RKCSB Leicester LE2 7LX, England ([email protected]).
(University of Wisconsin), Joseph Baur, PhD (University of Pennsylvania), Anait S. Levenson, MD, PhD (University of Mississippi), John Pezzuto, PhD (University of Hawaii at Hilo), and Ole Vang, PhD (Roskilde University, Denmark). 1. Semba RD, Ferrucci L, Bartali B, et al. Resveratrol levels and all-cause mortality in older community-dwelling adults. JAMA Intern Med. 2014;174(7): 1077-1084. 2. Roberts M. Red wine health benefits 'overhyped.' BBC News. May 12, 2014. http://www.bbc.co.uk/news/health-27371546. Accessed August 2014. 3. Calabrese EJ, Mattson MP, Calabrese V. Resveratrol commonly displays hormesis: occurrence and biomedical significance. Hum Exp Toxicol. 2010;29 (12):980-1015. 4. Baur JA, Pearson KJ, Price NL, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444(7117):337-342. 5. Yoshino J, Conte C, Fontana L, et al. Resveratrol supplementation does not improve metabolic function in nonobese women with normal glucose tolerance. Cell Metab. 2012;16(5):658-664.
Left Ventricular Noncompaction and Athletes: Looking for Stratification Criteria To the Editor We read with great interest the case report by Peritz et al1 about the distinction between hypertrabeculation and left ventricle noncompaction (LVNC) cardiomyopathy, especially in participants in competitive sports. In our opinion, and after reviewing literature, there are 2 matters of concern. First, as reported in a recently published series of 1146 athletes by Gati et al,2 athletes exhibit a higher prevalence of left ventricular trabeculation compared with controls. Therefore, for the diagnosis of LVNC in this population, we think that perhaps it would be necessary to take into account other factors such as familiar disease previously known, left ventricle dilatation and/or dysfunction, ventricular arrhythmias in Holter monitoring or during exercise testing, and the presence of late gadolinium hyperenhancement in cardiac magnetic resonance imaging as a marker of fibrosis. As Stöllberger et al3 mentioned, this is an important diagnostic dilemma, and given the further implications that diagnosis of LVNC implies, especially in athletes, standardization of diagnostic criteria is mandatory. Otherwise, as it happens in hypertrophic cardiomyopathy, several risk stratification criteria of sudden death should be considered for LVNC. Once the diagnosis is established following the classic criteria, different clinical scenarios of LVNC can be present, probably with different prognosis. Ventricular dysfunction, nonsustained ventricular tachycardia in Holter monitoring, and the presence of fibrosis should be considered as high-risk criteria.4 In conclusion, we think that to establish clear diagnosis criteria of hypertrabeculation vs LVNC is mandatory, and once LVNC is diagnosed, stratification criteria and follow-up is fundamental. Sandra Secades, MD Maria Martín, MD, PhD Cesar Morís, MD, PhD
Conflict of Interest Disclosures: None reported. Funding/Support: The authors’ research is supported by Cancer Research United Kingdom. Role of the Funder/Sponsor: Cancer Research United Kingdom had no role in the preparation, review, or approval of the manuscript or the decision to submit the manuscript for publication. Additional Contributions: We gratefully acknowledge suggestions and feedback during the preparation of this letter from Nihal Ahmad, PhD
Author Affiliations: Department of Cardiology, Hospital Universitario Central de Asturias, Oviedo, Spain. Corresponding Author: María Martín, MD, PhD, Department of Cardiology, Hospital Universitario Central de Asturias, Avda Pedro Masaveu 27, 4L Oviedo Asturias, Spain ([email protected]). Conflict of Interest Disclosures: None reported.
jamainternalmedicine.com
JAMA Internal Medicine January 2015 Volume 175, Number 1
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a J H Quillen College User on 05/28/2015
141
Letters
1. Peritz DC, Vaughn A, Ciocca M, Chung EH. Hypertrabeculation vs left ventricular noncompaction on echocardiogram: a reason to restrict athletic participation? JAMA Intern Med. 2014;174(8):1379-1382.
1. Peritz DC, Vaughn A, Ciocca M, Chung EH. Hypertrabeculation vs left ventricular noncompaction on echocardiogram: a reason to restrict athletic participation? JAMA Intern Med. 2014;174(8):1379-1382.
2. Gati S, Chandra N, Bennett RL, et al. Increased left ventricular trabeculation in highly trained athletes: do we need more stringent criteria for the diagnosis of left ventricular non-compaction in athletes? Heart. 2013;99(6):401-408.
2. Sheikh N, Sharma S. Impact of ethnicity on cardiac adaptation to exercise. Nat Rev Cardiol. 2014;11(4):198-217.
3. Stöllberger C, Finsterer J. A diagnostic dilemma in non-compaction, resulting in near expulsion from the Football World Cup. Eur J Echocardiogr. 2011;12(2):8.
3. Tizón-Marcos H, de la Paz Ricapito M, Pibarot P, et al. Characteristics of trabeculated myocardium burden in young and apparently healthy adults. Am J Cardiol. 2014;114(7):1094-1099.
4. Jenni R, Oechslin E, Schneider J, Attenhofer Jost C, Kaufmann PA. Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: a step towards classification as a distinct cardiomyopathy. Heart. 2001;86(6):666-671.
4. Gati S, Papadakis M, Papamichael ND, et al. Reversible de novo left ventricular trabeculations in pregnant women: implications for the diagnosis of left ventricular noncompaction in low-risk populations. Circulation. 2014;130(6): 475-483.
In Reply We thank Secades and colleagues for their interest in our case report.1 The diagnosis of left ventricular noncompaction (LVNC) carries with it significant consequences, especially for the competitive athlete of Afro-Caribbean descent.2 We agree that the current diagnostic criteria for LVNC are inadequate. Tizón-Marcos and colleagues 3 recently showed that healthy young men demonstrate a variable amount of trabeculation and an incidence of noncompaction cardiomyopathy greater than anticipated when applying the current criteria. We also agree that there needs to be better risk stratification. Reversibility, diastolic myocardial thickness and electrocardiography may be emerging risk stratification criteria. In a recently published study, Gati and colleagues4 demonstrated that increased trabeculation occurring in pregnancy resolved during the postpartum period. They theorized that increased trabeculation was not due to noncompaction but rather to a temporary elevation in left ventricular (LV) loading. This observation may be especially important in low-risk individuals noted to only have increased trabeculation, ie, those without LV systolic dysfunction, arrhythmias, and/or cardioembolic events. Myocardial diastolic thickness has also been proposed as an important diagnostic factor. Supported by elegant mathematical modeling, MacIver5 postulated that inadequate compaction and subsequent reduced wall thickness predispose the heart to increased wall stress. It is this increased wall stress that results in elevated myocardial strain and subsequent decreased LV function. Lastly, Steffel et al6 used electrocardiographic variations to determine which abnormalities were associated with poor long-term outcomes in patients with LVNC. Soon, the 36th Bethesda Conference will be updated, and we hope that this important document will be less restrictive on athletes with hypertrabeculation but preserved LV function. Continued research, focusing on exercise induced LV loading as a potential cause for hypertrabeculation, should help improve risk assessment and limit over diagnosis of LVNC in athletes. David C. Peritz, MD Eugene H. Chung, MD Author Affiliations: Department of Medicine/Pediatrics, University of North Carolina–Chapel Hill (Peritz); Division of Cardiology, Department of Medicine, University of North Carolina–Chapel Hill (Chung). Corresponding Author: David C. Peritz, MD, Department of Medicine/ Pediatrics, University of North Carolina–Chapel Hill, 160 Dental Cir, Campus Box 7075, Chapel Hill, NC 27599 ([email protected]). Conflict of Interest Disclosures: None reported.
142
5. MacIver DH. A new understanding and definition of non-compaction cardiomyopathy using analysis of left ventricular wall mechanics and stresses. Int J Cardiol. 2014;174(3):819-821. 6. Steffel J, Hürlimann D, Namdar M, et al. Long-term follow-up of patients with isolated left ventricular noncompaction: role of electrocardiography in predicting poor outcome. Circ J. 2011;75(7):1728-1734.
Criteria for Waiver of Informed Consent for Quality Improvement Research To the Editor Pletcher and colleagues1 addressed the important issue of informed consent in quality-improvement research. We have often faced the issue of whether a waiver of consent is justified in our research. For the last several years, we have used 3 guiding criteria. First, the research must be minimal risk. Although this seems self-evident for most quality-improvement projects, it should not be taken for granted. There is always a risk of loss of confidentiality, and for some sensitive topics such as human immunodeficiency virus care or substance use treatment, the risk of loss of confidentiality must be weighed against the advantages of conducting a study with a waiver of consent. Institutional review boards (IRBs) should ensure that proper safeguards are in place to prevent accidental disclosure of sensitive data (eg, extraction of data from the electronic health record without patient identifiers). In addition, IRBs should consider the risk to the control and usual care groups that will not receive a promising intervention, including (1) plans to provide the intervention to the control group after trial completion if it is successful and (2) whether the likelihood of benefit is high enough that it threatens equipoise and it would be unethical to conduct a traditional randomized clinical trial, in which case an alternative study design (eg, stepped wedge, time series) should be recommended. The second criterion is that it would not be possible to obtain informed consent without threatening the validity of the trial. This clearly applies when the process of obtaining consent would make a person aware that she needed a clinical service, eg, telling a patient that she is eligible for a study of outreach to improve colorectal cancer screening because she had not been screened.2 But, it is also appropriate to request a waiver of consent for effectiveness studies, which would be invalid if a minority of eligible patients consented to participate. Third, we require that all data for the study will be collected as part of routine care, including patient demographics, comorbidities, and outcomes. If additional data are needed from patients, we require that informed consent be obtained for the part of the study that requires these data.3 Using these principles, we believe it is possible to conduct large, rigorous, generalizable quality-improvement research while maintaining stringent protection for human participants. Because of
JAMA Internal Medicine January 2015 Volume 175, Number 1
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a J H Quillen College User on 05/28/2015
jamainternalmedicine.com
poured cold water over the idea that resveratrol as a dietary constituent prevents heart disease or cancer or prolongs life. The study suggests that the intake of red wine by elderly persons, as judged by urinary levels of resveratrol metabolites, did not affect overall mortality, incidence of cardiovascular disease or cancer, or biomarkers of incipient inflammation. This publication elicited considerable negative resonances in the international lay press (eg, “Red wine health benefits ‘overhyped’”).2 We submit that several aspects render the study unsuitable to warrant such negative resonance. Participants were classified into quartiles based on their urinary resveratrol metabolite levels measured once at the start of the study. We seriously doubt that this single value can accurately reflect lifetime exposure because the impact of resveratrol on health is likely to have been heavily influenced by consumption patterns prior to the investigation. The dose-response relationships that govern the efficacy of resveratrol are unclear and may display hormetic properties with opposing effects observed at small and large doses.3 In the study by Semba et al,1 the first quartile of urine levels contained values from participants who refrained from resveratrol consumption and those whose resveratrol intake was low, militating against the ability to tease out potential differences between resveratrol-naive participants and those with a low intake. Nutritional status of study participants is one of the many variables that affect disease prevention outcomes. Resveratrol is likely to engage its effects via subtle disturbances of abnormal cell metabolic processes associated with high fat intake typical of the Western diet.4 This means that resveratrol may cause its preventive efficacy only in individuals who have consistently ingested high amounts of fat and/or have the metabolic syndrome, but not in healthy ones.5 The article by Semba et al1 does not give any indication as to the amount of fat consumption by the participants. A quarter to a third of them were prediabetic or diabetic; assessment of study end points vs resveratrol consumption in this subgroup vis à vis the metabolically uncompromised participants might have been revealing. We believe that many more trials focusing on individuals characterized by a particular biochemical or pathological constitution or nutritional intake need to be performed before resveratrol can confidently be thrown out with the proverbial bath water. Karen Brown, PhD Alessandro Rufini, PhD Andreas Gescher, DSc Author Affiliations: Cancer Biomarkers and Prevention Group, Department of Cancer Studies, University of Leicester, Leicester, England. Corresponding Author: Andreas Gescher, DSc, Cancer Biomarkers and Prevention Group, Department of Cancer Studies, University of Leicester, RKCSB Leicester LE2 7LX, England ([email protected]).
(University of Wisconsin), Joseph Baur, PhD (University of Pennsylvania), Anait S. Levenson, MD, PhD (University of Mississippi), John Pezzuto, PhD (University of Hawaii at Hilo), and Ole Vang, PhD (Roskilde University, Denmark). 1. Semba RD, Ferrucci L, Bartali B, et al. Resveratrol levels and all-cause mortality in older community-dwelling adults. JAMA Intern Med. 2014;174(7): 1077-1084. 2. Roberts M. Red wine health benefits 'overhyped.' BBC News. May 12, 2014. http://www.bbc.co.uk/news/health-27371546. Accessed August 2014. 3. Calabrese EJ, Mattson MP, Calabrese V. Resveratrol commonly displays hormesis: occurrence and biomedical significance. Hum Exp Toxicol. 2010;29 (12):980-1015. 4. Baur JA, Pearson KJ, Price NL, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444(7117):337-342. 5. Yoshino J, Conte C, Fontana L, et al. Resveratrol supplementation does not improve metabolic function in nonobese women with normal glucose tolerance. Cell Metab. 2012;16(5):658-664.
Left Ventricular Noncompaction and Athletes: Looking for Stratification Criteria To the Editor We read with great interest the case report by Peritz et al1 about the distinction between hypertrabeculation and left ventricle noncompaction (LVNC) cardiomyopathy, especially in participants in competitive sports. In our opinion, and after reviewing literature, there are 2 matters of concern. First, as reported in a recently published series of 1146 athletes by Gati et al,2 athletes exhibit a higher prevalence of left ventricular trabeculation compared with controls. Therefore, for the diagnosis of LVNC in this population, we think that perhaps it would be necessary to take into account other factors such as familiar disease previously known, left ventricle dilatation and/or dysfunction, ventricular arrhythmias in Holter monitoring or during exercise testing, and the presence of late gadolinium hyperenhancement in cardiac magnetic resonance imaging as a marker of fibrosis. As Stöllberger et al3 mentioned, this is an important diagnostic dilemma, and given the further implications that diagnosis of LVNC implies, especially in athletes, standardization of diagnostic criteria is mandatory. Otherwise, as it happens in hypertrophic cardiomyopathy, several risk stratification criteria of sudden death should be considered for LVNC. Once the diagnosis is established following the classic criteria, different clinical scenarios of LVNC can be present, probably with different prognosis. Ventricular dysfunction, nonsustained ventricular tachycardia in Holter monitoring, and the presence of fibrosis should be considered as high-risk criteria.4 In conclusion, we think that to establish clear diagnosis criteria of hypertrabeculation vs LVNC is mandatory, and once LVNC is diagnosed, stratification criteria and follow-up is fundamental. Sandra Secades, MD Maria Martín, MD, PhD Cesar Morís, MD, PhD
Conflict of Interest Disclosures: None reported. Funding/Support: The authors’ research is supported by Cancer Research United Kingdom. Role of the Funder/Sponsor: Cancer Research United Kingdom had no role in the preparation, review, or approval of the manuscript or the decision to submit the manuscript for publication. Additional Contributions: We gratefully acknowledge suggestions and feedback during the preparation of this letter from Nihal Ahmad, PhD
Author Affiliations: Department of Cardiology, Hospital Universitario Central de Asturias, Oviedo, Spain. Corresponding Author: María Martín, MD, PhD, Department of Cardiology, Hospital Universitario Central de Asturias, Avda Pedro Masaveu 27, 4L Oviedo Asturias, Spain ([email protected]). Conflict of Interest Disclosures: None reported.
jamainternalmedicine.com
JAMA Internal Medicine January 2015 Volume 175, Number 1
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a J H Quillen College User on 05/28/2015
141
Letters
1. Peritz DC, Vaughn A, Ciocca M, Chung EH. Hypertrabeculation vs left ventricular noncompaction on echocardiogram: a reason to restrict athletic participation? JAMA Intern Med. 2014;174(8):1379-1382.
1. Peritz DC, Vaughn A, Ciocca M, Chung EH. Hypertrabeculation vs left ventricular noncompaction on echocardiogram: a reason to restrict athletic participation? JAMA Intern Med. 2014;174(8):1379-1382.
2. Gati S, Chandra N, Bennett RL, et al. Increased left ventricular trabeculation in highly trained athletes: do we need more stringent criteria for the diagnosis of left ventricular non-compaction in athletes? Heart. 2013;99(6):401-408.
2. Sheikh N, Sharma S. Impact of ethnicity on cardiac adaptation to exercise. Nat Rev Cardiol. 2014;11(4):198-217.
3. Stöllberger C, Finsterer J. A diagnostic dilemma in non-compaction, resulting in near expulsion from the Football World Cup. Eur J Echocardiogr. 2011;12(2):8.
3. Tizón-Marcos H, de la Paz Ricapito M, Pibarot P, et al. Characteristics of trabeculated myocardium burden in young and apparently healthy adults. Am J Cardiol. 2014;114(7):1094-1099.
4. Jenni R, Oechslin E, Schneider J, Attenhofer Jost C, Kaufmann PA. Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: a step towards classification as a distinct cardiomyopathy. Heart. 2001;86(6):666-671.
4. Gati S, Papadakis M, Papamichael ND, et al. Reversible de novo left ventricular trabeculations in pregnant women: implications for the diagnosis of left ventricular noncompaction in low-risk populations. Circulation. 2014;130(6): 475-483.
In Reply We thank Secades and colleagues for their interest in our case report.1 The diagnosis of left ventricular noncompaction (LVNC) carries with it significant consequences, especially for the competitive athlete of Afro-Caribbean descent.2 We agree that the current diagnostic criteria for LVNC are inadequate. Tizón-Marcos and colleagues 3 recently showed that healthy young men demonstrate a variable amount of trabeculation and an incidence of noncompaction cardiomyopathy greater than anticipated when applying the current criteria. We also agree that there needs to be better risk stratification. Reversibility, diastolic myocardial thickness and electrocardiography may be emerging risk stratification criteria. In a recently published study, Gati and colleagues4 demonstrated that increased trabeculation occurring in pregnancy resolved during the postpartum period. They theorized that increased trabeculation was not due to noncompaction but rather to a temporary elevation in left ventricular (LV) loading. This observation may be especially important in low-risk individuals noted to only have increased trabeculation, ie, those without LV systolic dysfunction, arrhythmias, and/or cardioembolic events. Myocardial diastolic thickness has also been proposed as an important diagnostic factor. Supported by elegant mathematical modeling, MacIver5 postulated that inadequate compaction and subsequent reduced wall thickness predispose the heart to increased wall stress. It is this increased wall stress that results in elevated myocardial strain and subsequent decreased LV function. Lastly, Steffel et al6 used electrocardiographic variations to determine which abnormalities were associated with poor long-term outcomes in patients with LVNC. Soon, the 36th Bethesda Conference will be updated, and we hope that this important document will be less restrictive on athletes with hypertrabeculation but preserved LV function. Continued research, focusing on exercise induced LV loading as a potential cause for hypertrabeculation, should help improve risk assessment and limit over diagnosis of LVNC in athletes. David C. Peritz, MD Eugene H. Chung, MD Author Affiliations: Department of Medicine/Pediatrics, University of North Carolina–Chapel Hill (Peritz); Division of Cardiology, Department of Medicine, University of North Carolina–Chapel Hill (Chung). Corresponding Author: David C. Peritz, MD, Department of Medicine/ Pediatrics, University of North Carolina–Chapel Hill, 160 Dental Cir, Campus Box 7075, Chapel Hill, NC 27599 ([email protected]). Conflict of Interest Disclosures: None reported.
142
5. MacIver DH. A new understanding and definition of non-compaction cardiomyopathy using analysis of left ventricular wall mechanics and stresses. Int J Cardiol. 2014;174(3):819-821. 6. Steffel J, Hürlimann D, Namdar M, et al. Long-term follow-up of patients with isolated left ventricular noncompaction: role of electrocardiography in predicting poor outcome. Circ J. 2011;75(7):1728-1734.
Criteria for Waiver of Informed Consent for Quality Improvement Research To the Editor Pletcher and colleagues1 addressed the important issue of informed consent in quality-improvement research. We have often faced the issue of whether a waiver of consent is justified in our research. For the last several years, we have used 3 guiding criteria. First, the research must be minimal risk. Although this seems self-evident for most quality-improvement projects, it should not be taken for granted. There is always a risk of loss of confidentiality, and for some sensitive topics such as human immunodeficiency virus care or substance use treatment, the risk of loss of confidentiality must be weighed against the advantages of conducting a study with a waiver of consent. Institutional review boards (IRBs) should ensure that proper safeguards are in place to prevent accidental disclosure of sensitive data (eg, extraction of data from the electronic health record without patient identifiers). In addition, IRBs should consider the risk to the control and usual care groups that will not receive a promising intervention, including (1) plans to provide the intervention to the control group after trial completion if it is successful and (2) whether the likelihood of benefit is high enough that it threatens equipoise and it would be unethical to conduct a traditional randomized clinical trial, in which case an alternative study design (eg, stepped wedge, time series) should be recommended. The second criterion is that it would not be possible to obtain informed consent without threatening the validity of the trial. This clearly applies when the process of obtaining consent would make a person aware that she needed a clinical service, eg, telling a patient that she is eligible for a study of outreach to improve colorectal cancer screening because she had not been screened.2 But, it is also appropriate to request a waiver of consent for effectiveness studies, which would be invalid if a minority of eligible patients consented to participate. Third, we require that all data for the study will be collected as part of routine care, including patient demographics, comorbidities, and outcomes. If additional data are needed from patients, we require that informed consent be obtained for the part of the study that requires these data.3 Using these principles, we believe it is possible to conduct large, rigorous, generalizable quality-improvement research while maintaining stringent protection for human participants. Because of
JAMA Internal Medicine January 2015 Volume 175, Number 1
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a J H Quillen College User on 05/28/2015
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