Abstract

Imaging the retinal vasculature offers a surrogate view of systemic vascular health, allowing noninvasive and longitudinal assessment of vascular pathology. The earliest anomalies in vascular disease arise in the microvasculature, however current imaging methods lack the spatiotemporal resolution to track blood flow at the capillary level. We report here on novel imaging technology that allows direct, noninvasive optical imaging of erythrocyte flow in human retinal capillaries. This was made possible using adaptive optics for high spatial resolution (1.5 μm), sCMOS camera technology for high temporal resolution (460 fps), and tunable wavebands from a broadband laser for maximal erythrocyte contrast. Particle image velocimetry on our data sequences was used to quantify flow. We observed marked spatiotemporal variability in velocity, which ranged from 0.3 to 3.3 mm/s, and changed by up to a factor of 4 in a given capillary during the 130 ms imaging period. Both mean and standard deviation across the imaged capillary network varied markedly with time, yet their ratio remained a relatively constant parameter (0.50 ± 0.056). Our observations concur with previous work using less direct methods, validating this as an investigative tool for the study of microvascular disease in humans.

© 2012 OSA

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  4. M. L. Baker, P. J. Hand, J. J. Wang, and T. Y. Wong, “Retinal signs and stroke: revisiting the link between the eye and brain,” Stroke39(4), 1371–1379 (2008).
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  6. K. M. Rose, T. Y. Wong, A. P. Carson, D. J. Couper, R. Klein, and A. R. Sharrett, “Migraine and retinal microvascular abnormalities: the Atherosclerosis Risk in Communities Study,” Neurology68(20), 1694–1700 (2007).
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  7. P. Gasser and J. Flammer, “Blood-cell velocity in the nailfold capillaries of patients with normal-tension and high-tension glaucoma,” Am. J. Ophthalmol.111(5), 585–588 (1991).
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  9. G. G. Pietra, F. Capron, S. Stewart, O. Leone, M. Humbert, I. M. Robbins, L. M. Reid, and R. M. Tuder, “Pathologic assessment of vasculopathies in pulmonary hypertension,” J. Am. Coll. Cardiol.43(12Suppl S), S25–S32 (2004).
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  25. J. Tam, P. Tiruveedhula, and A. Roorda, “Characterization of single-file flow through human retinal parafoveal capillaries using an adaptive optics scanning laser ophthalmoscope,” Biomed. Opt. Express2(4), 781–793 (2011).
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    [CrossRef] [PubMed]
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  28. K. Miyamoto and Y. Ogura, “Pathogenetic potential of leukocytes in diabetic retinopathy,” Semin. Ophthalmol.14(4), 233–239 (1999).
    [CrossRef] [PubMed]
  29. G. W. Schmid-Schönbein, Y. Y. Shih, and S. Chien, “Morphometry of human leukocytes,” Blood56(5), 866–875 (1980).
    [PubMed]
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    [PubMed]
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    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
  36. R. D. Frostig, E. E. Lieke, D. Y. Ts’o, and A. Grinvald, “Cortical functional architecture and local coupling between neuronal activity and the microcirculation revealed by in vivo high-resolution optical imaging of intrinsic signals,” Proc. Natl. Acad. Sci. U.S.A.87(16), 6082–6086 (1990).
    [CrossRef] [PubMed]
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    [PubMed]
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    [CrossRef] [PubMed]
  43. M. Iwasaki and H. Inomata, “Relation between superficial capillaries and foveal structures in the human retina,” Invest. Ophthalmol. Vis. Sci.27(12), 1698–1705 (1986).
    [PubMed]
  44. Y. C. Fung, “Stochastic flow in capillary blood vessels,” Microvasc. Res.5(1), 34–48 (1973).
    [CrossRef] [PubMed]
  45. P. C. Johnson and H. Wayland, “Regulation of blood flow in single capillaries,” Am. J. Physiol.212(6), 1405–1415 (1967).
    [PubMed]
  46. G. Pawlik, A. Rackl, and R. J. Bing, “Quantitative capillary topography and blood flow in the cerebral cortex of cats: an in vivo microscopic study,” Brain Res.208(1), 35–58 (1981).
    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
  48. Y. C. Fung, “Blood flow in the capillary bed,” J. Biomech.2(4), 353–372 (1969).
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  49. D. Cousineau, C. P. Rose, D. Lamoureux, and C. A. Goresky, “Changes in cardiac transcapillary exchange with metabolic coronary vasodilation in the intact dog,” Circ. Res.53(6), 719–730 (1983).
    [CrossRef] [PubMed]
  50. I. Krolo and A. G. Hudetz, “Hypoxemia alters erythrocyte perfusion pattern in the cerebral capillary network,” Microvasc. Res.59(1), 72–79 (2000).
    [CrossRef] [PubMed]
  51. M. L. Schulte, J. D. Wood, and A. G. Hudetz, “Cortical electrical stimulation alters erythrocyte perfusion pattern in the cerebral capillary network of the rat,” Brain Res.963(1-2), 81–92 (2003).
    [CrossRef] [PubMed]
  52. J. Vogel and W. Kuschinsky, “Decreased heterogeneity of capillary plasma flow in the rat whisker-barrel cortex during functional hyperemia,” J. Cereb. Blood Flow Metab.16(6), 1300–1306 (1996).
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    [CrossRef] [PubMed]
  55. S. S. Segal, “Regulation of blood flow in the microcirculation,” Microcirculation12(1), 33–45 (2005).
    [CrossRef] [PubMed]
  56. M. M. Guest, T. P. Bond, R. G. Cooper, and J. R. Derrick, “Red Blood Cells: Change in Shape in Capillaries,” Science142(3597), 1319–1321 (1963).
    [CrossRef] [PubMed]
  57. F. Grubbs, “Procedures for detecting outlying observations in samples,” Technometrics11(1), 1–21 (1969).
    [CrossRef]
  58. D. Cook, “Detection of influential observations in linear regression,” Technometrics19(1), 15–18 (1977).
    [CrossRef]

2012

M. K. Ikram, C. Y. Cheung, T. Y. Wong, and C. P. Chen, “Retinal pathology as biomarker for cognitive impairment and Alzheimer’s disease,” J. Neurol. Neurosurg. Psychiatry83(9), 917–922 (2012).
[CrossRef] [PubMed]

V. J. Srinivasan, H. Radhakrishnan, E. H. Lo, E. T. Mandeville, J. Y. Jiang, S. Barry, and A. E. Cable, “OCT methods for capillary velocimetry,” Biomed. Opt. Express3(3), 612–629 (2012).
[CrossRef] [PubMed]

Z. Zhong, G. Huang, T. Y. Chui, B. L. Petrig, and S. A. Burns, “Local flicker stimulation evokes local retinal blood velocity changes,” J. Vis.12(6), 3 (2012).
[CrossRef] [PubMed]

P. Bedggood and A. Metha, “Variability in bleach kinetics and amount of photopigment between individual foveal cones,” Invest. Ophthalmol. Vis. Sci.53(7), 3673–3681 (2012).
[CrossRef] [PubMed]

S. N. Jespersen and L. Østergaard, “The roles of cerebral blood flow, capillary transit time heterogeneity, and oxygen tension in brain oxygenation and metabolism,” J. Cereb. Blood Flow Metab.32(2), 264–277 (2012).
[CrossRef] [PubMed]

2011

Z. Zhong, H. Song, T. Y. Chui, B. L. Petrig, and S. A. Burns, “Noninvasive measurements and analysis of blood velocity profiles in human retinal vessels,” Invest. Ophthalmol. Vis. Sci.52(7), 4151–4157 (2011).
[CrossRef] [PubMed]

J. Tam, P. Tiruveedhula, and A. Roorda, “Characterization of single-file flow through human retinal parafoveal capillaries using an adaptive optics scanning laser ophthalmoscope,” Biomed. Opt. Express2(4), 781–793 (2011).
[CrossRef] [PubMed]

J. Tam, K. P. Dhamdhere, P. Tiruveedhula, S. Manzanera, S. Barez, M. A. Bearse, A. J. Adams, and A. Roorda, “Disruption of the retinal parafoveal capillary network in type 2 diabetes before the onset of diabetic retinopathy,” Invest. Ophthalmol. Vis. Sci.52(12), 9257–9266 (2011).
[CrossRef] [PubMed]

2010

J. Tam, J. A. Martin, and A. Roorda, “Noninvasive visualization and analysis of parafoveal capillaries in humans,” Invest. Ophthalmol. Vis. Sci.51(3), 1691–1698 (2010).
[CrossRef] [PubMed]

2009

J. A. Martin and A. Roorda, “Pulsatility of parafoveal capillary leukocytes,” Exp. Eye Res.88(3), 356–360 (2009).
[CrossRef] [PubMed]

2008

Y. Wang, B. A. Bower, J. A. Izatt, O. Tan, and D. Huang, “Retinal blood flow measurement by circumpapillary Fourier domain Doppler optical coherence tomography,” J. Biomed. Opt.13(6), 064003 (2008).
[CrossRef] [PubMed]

M. L. Baker, P. J. Hand, J. J. Wang, and T. Y. Wong, “Retinal signs and stroke: revisiting the link between the eye and brain,” Stroke39(4), 1371–1379 (2008).
[CrossRef] [PubMed]

Z. Zhong, B. L. Petrig, X. Qi, and S. A. Burns, “In vivo measurement of erythrocyte velocity and retinal blood flow using adaptive optics scanning laser ophthalmoscopy,” Opt. Express16(17), 12746–12756 (2008).
[CrossRef] [PubMed]

2007

K. M. Rose, T. Y. Wong, A. P. Carson, D. J. Couper, R. Klein, and A. R. Sharrett, “Migraine and retinal microvascular abnormalities: the Atherosclerosis Risk in Communities Study,” Neurology68(20), 1694–1700 (2007).
[CrossRef] [PubMed]

R. Chibber, B. M. Ben-Mahmud, S. Chibber, and E. M. Kohner, “Leukocytes in diabetic retinopathy,” Curr. Diabetes Rev.3(1), 3–14 (2007).
[CrossRef] [PubMed]

F. C. Delori, R. H. Webb, D. H. Sliney, and American National Standards Institute, “Maximum permissible exposures for ocular safety (ANSI 2000), with emphasis on ophthalmic devices,” J. Opt. Soc. Am. A24(5), 1250–1265 (2007).
[CrossRef] [PubMed]

2005

J. A. Martin and A. Roorda, “Direct and noninvasive assessment of parafoveal capillary leukocyte velocity,” Ophthalmology112(12), 2219–2224 (2005).
[CrossRef] [PubMed]

N. Patton, T. Aslam, T. Macgillivray, A. Pattie, I. J. Deary, and B. Dhillon, “Retinal vascular image analysis as a potential screening tool for cerebrovascular disease: a rationale based on homology between cerebral and retinal microvasculatures,” J. Anat.206(4), 319–348 (2005).
[CrossRef] [PubMed]

S. S. Segal, “Regulation of blood flow in the microcirculation,” Microcirculation12(1), 33–45 (2005).
[CrossRef] [PubMed]

2004

G. G. Pietra, F. Capron, S. Stewart, O. Leone, M. Humbert, I. M. Robbins, L. M. Reid, and R. M. Tuder, “Pathologic assessment of vasculopathies in pulmonary hypertension,” J. Am. Coll. Cardiol.43(12Suppl S), S25–S32 (2004).
[CrossRef] [PubMed]

J. C. de la Torre, “Is Alzheimer’s disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics,” Lancet Neurol.3(3), 184–190 (2004).
[CrossRef] [PubMed]

2003

B. White, M. Pierce, N. Nassif, B. Cense, B. Park, G. Tearney, B. Bouma, T. Chen, and J. de Boer, “In vivo dynamic human retinal blood flow imaging using ultra-high-speed spectral domain optical coherence tomography,” Opt. Express11(25), 3490–3497 (2003).
[CrossRef] [PubMed]

M. L. Schulte, J. D. Wood, and A. G. Hudetz, “Cortical electrical stimulation alters erythrocyte perfusion pattern in the cerebral capillary network of the rat,” Brain Res.963(1-2), 81–92 (2003).
[CrossRef] [PubMed]

2002

B. Falsini, C. E. Riva, and E. Logean, “Flicker-evoked changes in human optic nerve blood flow: relationship with retinal neural activity,” Invest. Ophthalmol. Vis. Sci.43(7), 2309–2316 (2002).
[PubMed]

2000

H. K. Rucker, H. J. Wynder, and W. E. Thomas, “Cellular mechanisms of CNS pericytes,” Brain Res. Bull.51(5), 363–369 (2000).
[CrossRef] [PubMed]

I. Krolo and A. G. Hudetz, “Hypoxemia alters erythrocyte perfusion pattern in the cerebral capillary network,” Microvasc. Res.59(1), 72–79 (2000).
[CrossRef] [PubMed]

K. Yaoeda, M. Shirakashi, S. Funaki, H. Funaki, T. Nakatsue, and H. Abe, “Measurement of microcirculation in the optic nerve head by laser speckle flowgraphy and scanning laser Doppler flowmetry,” Am. J. Ophthalmol.129(6), 734–739 (2000).
[CrossRef] [PubMed]

1999

K. Miyamoto and Y. Ogura, “Pathogenetic potential of leukocytes in diabetic retinopathy,” Semin. Ophthalmol.14(4), 233–239 (1999).
[CrossRef] [PubMed]

H. A. Quigley, “Neuronal death in glaucoma,” Prog. Retin. Eye Res.18(1), 39–57 (1999).
[CrossRef] [PubMed]

1998

A. Harris, L. Kagemann, and G. A. Cioffi, “Assessment of human ocular hemodynamics,” Surv. Ophthalmol.42(6), 509–533 (1998).
[CrossRef] [PubMed]

1997

J. Liang, D. R. Williams, and D. T. Miller, “Supernormal vision and high-resolution retinal imaging through adaptive optics,” J. Opt. Soc. Am. A14(11), 2884–2892 (1997).
[CrossRef] [PubMed]

B. P. Helmke, S. N. Bremner, B. W. Zweifach, R. Skalak, and G. W. Schmid-Schönbein, “Mechanisms for increased blood flow resistance due to leukocytes,” Am. J. Physiol.273(6 Pt 2), H2884–H2890 (1997).
[PubMed]

A. G. Hudetz, “Blood flow in the cerebral capillary network: a review emphasizing observations with intravital microscopy,” Microcirculation4(2), 233–252 (1997).
[CrossRef] [PubMed]

1996

J. Vogel and W. Kuschinsky, “Decreased heterogeneity of capillary plasma flow in the rat whisker-barrel cortex during functional hyperemia,” J. Cereb. Blood Flow Metab.16(6), 1300–1306 (1996).
[CrossRef] [PubMed]

J. Briers, “Laser Doppler and time-varying speckle: a reconciliation,” J. Opt. Soc. Am. A13(2), 345–350 (1996).
[CrossRef]

1994

A. Villringer, A. Them, U. Lindauer, K. Einhäupl, and U. Dirnagl, “Capillary perfusion of the rat brain cortex. An in vivo confocal microscopy study,” Circ. Res.75(1), 55–62 (1994).
[CrossRef] [PubMed]

1992

R. Keane and R. Adrian, “Theory of cross-correlation analysis of PIV images,” Appl. Sci. Res.49(3), 191–215 (1992).
[CrossRef]

1991

S. Wolf, O. Arend, H. Toonen, B. Bertram, F. Jung, and M. Reim, “Retinal capillary blood flow measurement with a scanning laser ophthalmoscope. Preliminary results,” Ophthalmology98(6), 996–1000 (1991).
[PubMed]

G. J. del Zoppo, G. W. Schmid-Schönbein, E. Mori, B. R. Copeland, and C. M. Chang, “Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons,” Stroke22(10), 1276–1283 (1991).
[CrossRef] [PubMed]

P. Gasser and O. Meienberg, “Finger microcirculation in classical migraine. A video-microscopic study of nailfold capillaries,” Eur. Neurol.31(3), 168–171 (1991).
[CrossRef] [PubMed]

P. Gasser and J. Flammer, “Blood-cell velocity in the nailfold capillaries of patients with normal-tension and high-tension glaucoma,” Am. J. Ophthalmol.111(5), 585–588 (1991).
[PubMed]

1990

R. D. Frostig, E. E. Lieke, D. Y. Ts’o, and A. Grinvald, “Cortical functional architecture and local coupling between neuronal activity and the microcirculation revealed by in vivo high-resolution optical imaging of intrinsic signals,” Proc. Natl. Acad. Sci. U.S.A.87(16), 6082–6086 (1990).
[CrossRef] [PubMed]

1986

M. Iwasaki and H. Inomata, “Relation between superficial capillaries and foveal structures in the human retina,” Invest. Ophthalmol. Vis. Sci.27(12), 1698–1705 (1986).
[PubMed]

1983

D. Cousineau, C. P. Rose, D. Lamoureux, and C. A. Goresky, “Changes in cardiac transcapillary exchange with metabolic coronary vasodilation in the intact dog,” Circ. Res.53(6), 719–730 (1983).
[CrossRef] [PubMed]

H. H. Parving, G. C. Viberti, H. Keen, J. S. Christiansen, and N. A. Lassen, “Hemodynamic factors in the genesis of diabetic microangiopathy,” Metabolism32(9), 943–949 (1983).
[CrossRef] [PubMed]

1982

C. E. Riva, J. E. Grunwald, and S. H. Sinclair, “Laser Doppler measurement of relative blood velocity in the human optic nerve head,” Invest. Ophthalmol. Vis. Sci.22(2), 241–248 (1982).
[PubMed]

1981

G. Pawlik, A. Rackl, and R. J. Bing, “Quantitative capillary topography and blood flow in the cerebral cortex of cats: an in vivo microscopic study,” Brain Res.208(1), 35–58 (1981).
[CrossRef] [PubMed]

1980

G. W. Schmid-Schönbein, Y. Y. Shih, and S. Chien, “Morphometry of human leukocytes,” Blood56(5), 866–875 (1980).
[PubMed]

1977

D. Cook, “Detection of influential observations in linear regression,” Technometrics19(1), 15–18 (1977).
[CrossRef]

1974

T. Tanaka, C. Riva, and B. Ben-Sira, “Blood velocity measurements in human retinal vessels,” Science186(4166), 830–831 (1974).
[CrossRef] [PubMed]

1973

Y. C. Fung, “Stochastic flow in capillary blood vessels,” Microvasc. Res.5(1), 34–48 (1973).
[CrossRef] [PubMed]

1969

Y. C. Fung, “Blood flow in the capillary bed,” J. Biomech.2(4), 353–372 (1969).
[CrossRef] [PubMed]

F. Grubbs, “Procedures for detecting outlying observations in samples,” Technometrics11(1), 1–21 (1969).
[CrossRef]

1967

P. C. Johnson and H. Wayland, “Regulation of blood flow in single capillaries,” Am. J. Physiol.212(6), 1405–1415 (1967).
[PubMed]

1963

M. M. Guest, T. P. Bond, R. G. Cooper, and J. R. Derrick, “Red Blood Cells: Change in Shape in Capillaries,” Science142(3597), 1319–1321 (1963).
[CrossRef] [PubMed]

1892

R. Gunn, “Ophthalmoscopic evidence of (1) arterial changes associated with chronic renal diseases and (2) of increased arterial tension,” Trans. Ophthalmol. Soc. U. K.12, 124–125 (1892).

1890

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M. K. Ikram, C. Y. Cheung, T. Y. Wong, and C. P. Chen, “Retinal pathology as biomarker for cognitive impairment and Alzheimer’s disease,” J. Neurol. Neurosurg. Psychiatry83(9), 917–922 (2012).
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R. Chibber, B. M. Ben-Mahmud, S. Chibber, and E. M. Kohner, “Leukocytes in diabetic retinopathy,” Curr. Diabetes Rev.3(1), 3–14 (2007).
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Supplementary Material (2)

» Media 1: MOV (1686 KB)     
» Media 2: MOV (1682 KB)     

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Figures (7)

Fig. 1
Fig. 1

Area of analysis. Top: Conventional fundus image (color) overlaid with an adaptive optics montage of the capillary network surrounding the foveal avascular zone (grayscale). A, V denotes arteries and veins. Bottom: Shows inset demarcated by yellow border in top. Arrows indicate direction of erythrocyte flow. Lower case letters denote capillary segments discussed in the text below. This is a region of high confluence, with 2 neighboring arterioles (A) delivering blood in opposing directions.

Fig. 2
Fig. 2

Sample of our imaging data. Top: a single frame at 593 nm, 1° nasal and 2° inferior to the foveal center, close to the edge of the foveal avascular zone. Bottom: Motion contrast enhancement of the same area, based on 60 frames of data (130 ms). The sequence itself is shown in Media 1.

Fig. 3
Fig. 3

Phantom data set for validation of measured velocities, consisting of 7 modeled capillaries. Grayscale: a single frame from the phantom data sequence. Modeled erythrocyte clusters are visible as dark rectangular patches. Color overlay: Velocity vectors in each region of interest. Speed is denoted both by arrow length and color. Numbers: median velocity ± median absolute difference (true velocity). Units are mm/s. Velocity measurements were derived by considering a line of points (minimum 10 per vessel) that were closest to the vessel center.

Fig. 4
Fig. 4

PIV analysis (median velocity) from the same image sequence as in Fig. 2 (Media 1). Imaging wavelength was 593 nm, imaged area was 1° nasal and 2° inferior to the foveal center. Diameter of displayed region is ~0.8 x 0.2°. Grayscale: motion contrast enhanced “division” image [38] from this sequence. Color arrows: Velocity vectors in each region of interest. Speed is denoted both by arrow length and color. Letters: Labeled capillary segments referred to in the text; labels correspond to those in Fig. 1.

Fig. 5
Fig. 5

PIV analysis (standard deviation) from an image sequence showing marked variability of flow over time, as well as location. The corresponding sequence is shown in Media 2. Grayscale: motion contrast enhanced “division” image [38] from this sequence. Color arrows: Standard deviation of velocity in time, using temporal windows 15 frames (33 ms) long. Standard deviation is denoted both by arrow length and color. Letters: Labeled capillary segments referred to in the text; labels correspond to those in Fig. 1.

Fig. 6
Fig. 6

Velocity in each capillary segment in the same image sequence shown in Fig. 5 (Media 2). Velocity generally increased throughout the course of this sequence. Blue plots indicate capillary segments e, g, m and w that were present in all sequences, and are analyzed in Fig. 7. Red plots indicate segments a (asterisks) and u (crosses), which are consecutive and are referred to in the text.

Fig. 7
Fig. 7

Velocity in the same 4 capillary segments across 5 image sequences. Each panel corresponds to the same capillary segment, and each plot color corresponds to the same image sequence.

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