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Erschienen in: Japanese Journal of Ophthalmology 3/2018

19.02.2018 | Clinical Investigation

Association between characteristics of foveal cystoid spaces and short-term responsiveness to ranibizumab for diabetic macular edema

verfasst von: Tomoaki Murakami, Kiyoshi Suzuma, Akihito Uji, Shin Yoshitake, Yoko Dodo, Masahiro Fujimoto, Tatsuya Yoshitake, Yuko Miwa, Nagahisa Yoshimura

Erschienen in: Japanese Journal of Ophthalmology | Ausgabe 3/2018

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Abstract

Purpose

To investigate the association between the characteristics of foveal cystoid spaces and short-term responsiveness to ranibizumab treatment for diabetic macular edema (DME) at 3 months from the initial injection.

Methods

We retrospectively reviewed 66 eyes of 61 patients with center-involved DME who received three consecutive ranibizumab injections and following as-needed administrations. We evaluated the relationship between visual improvement at 3 months and the preoperative optical coherence tomography (OCT) parameters including hyperreflective foci, heterogeneous OCT reflectivity, mean levels of OCT reflectivity and height of foveal cystoid spaces.

Results

Twenty-three eyes without preoperative hyperreflective foci in the foveal cystoid spaces had significantly greater improvement in the logarithm of the minimum angle of resolution visual acuity (logMAR VA) at 3 months than 43 eyes with foci (P = 0.006). That was similar to the greater reduction in CSF thickness in eyes without lesions after treatment at the same time point (P < 0.001). VA improvement at 3 months was not associated with the height (R = 0.215, P = 0.083) or the reflectivity levels (R = -0.079, P = 0.538) of foveal cystoid spaces. There were no differences in VA changes between eyes with and without heterogeneous reflectivity in foveal cystoid spaces (P = 0.297). Multivariate analyses showed that logMAR VA and the absence of hyperreflective foci in foveal cystoid spaces were associated with VA improvement at 3 months.

Conclusion

Hyperreflective foci in foveal cystoid spaces at baseline predict poorer short-term responsiveness to ranibizumab injections for DME.
Literatur
1.
Zurück zum Zitat Yau JW, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35:556–64.CrossRefPubMedPubMedCentral Yau JW, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35:556–64.CrossRefPubMedPubMedCentral
2.
3.
Zurück zum Zitat Gardner TW, Antonetti DA, Barber AJ, LaNoue KF, Levison SW. Diabetic retinopathy: more than meets the eye. Surv Ophthalmol. 2002;47(Suppl 2):S253–62.CrossRefPubMed Gardner TW, Antonetti DA, Barber AJ, LaNoue KF, Levison SW. Diabetic retinopathy: more than meets the eye. Surv Ophthalmol. 2002;47(Suppl 2):S253–62.CrossRefPubMed
4.
Zurück zum Zitat Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331:1480–7.CrossRefPubMed Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331:1480–7.CrossRefPubMed
5.
Zurück zum Zitat Funatsu H, Yamashita H, Noma H, Mimura T, Yamashita T, Hori S. Increased levels of vascular endothelial growth factor and interleukin-6 in the aqueous humor of diabetics with macular edema. Am J Ophthalmol. 2002;133:70–7.CrossRefPubMed Funatsu H, Yamashita H, Noma H, Mimura T, Yamashita T, Hori S. Increased levels of vascular endothelial growth factor and interleukin-6 in the aqueous humor of diabetics with macular edema. Am J Ophthalmol. 2002;133:70–7.CrossRefPubMed
6.
Zurück zum Zitat Murakami T, Frey T, Lin C, Antonetti DA. Protein kinase cbeta phosphorylates occludin regulating tight junction trafficking in vascular endothelial growth factor-induced permeability in vivo. Diabetes. 2012;61:1573–83.CrossRefPubMedPubMedCentral Murakami T, Frey T, Lin C, Antonetti DA. Protein kinase cbeta phosphorylates occludin regulating tight junction trafficking in vascular endothelial growth factor-induced permeability in vivo. Diabetes. 2012;61:1573–83.CrossRefPubMedPubMedCentral
7.
Zurück zum Zitat Cunningham ET Jr, Adamis AP, Altaweel M, Aiello LP, Bressler NM, D’Amico DJ, et al. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology. 2005;112:1747–57.CrossRefPubMed Cunningham ET Jr, Adamis AP, Altaweel M, Aiello LP, Bressler NM, D’Amico DJ, et al. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology. 2005;112:1747–57.CrossRefPubMed
8.
Zurück zum Zitat Haritoglou C, Kook D, Neubauer A, Wolf A, Priglinger S, Strauss R, et al. Intravitreal bevacizumab (Avastin) therapy for persistent diffuse diabetic macular edema. Retina. 2006;26:999–1005.CrossRefPubMed Haritoglou C, Kook D, Neubauer A, Wolf A, Priglinger S, Strauss R, et al. Intravitreal bevacizumab (Avastin) therapy for persistent diffuse diabetic macular edema. Retina. 2006;26:999–1005.CrossRefPubMed
9.
Zurück zum Zitat Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO, et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118:615–25.CrossRefPubMed Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO, et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118:615–25.CrossRefPubMed
10.
Zurück zum Zitat Do DV, Schmidt-Erfurth U, Gonzalez VH, Gordon CM, Tolentino M, Berliner AJ, et al. The Da Vinci study: phase 2 primary results of VEGF trap-eye in patients with diabetic macular edema. Ophthalmology. 2011;118:1819–26.CrossRefPubMed Do DV, Schmidt-Erfurth U, Gonzalez VH, Gordon CM, Tolentino M, Berliner AJ, et al. The Da Vinci study: phase 2 primary results of VEGF trap-eye in patients with diabetic macular edema. Ophthalmology. 2011;118:1819–26.CrossRefPubMed
11.
Zurück zum Zitat Wells JA, Glassman AR, Ayala AR, Jampol LM, Aiello LP, Antoszyk AN, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372:1193–203.CrossRefPubMed Wells JA, Glassman AR, Ayala AR, Jampol LM, Aiello LP, Antoszyk AN, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372:1193–203.CrossRefPubMed
12.
Zurück zum Zitat Ogura Y, Shiraga F, Terasaki H, Ohji M, Ishida S, Sakamoto T, et al. Clinical practice pattern in management of diabetic macular edema in Japan: survey results of Japanese retinal specialists. Jpn J Ophthalmol. 2017;61:43–50.CrossRefPubMed Ogura Y, Shiraga F, Terasaki H, Ohji M, Ishida S, Sakamoto T, et al. Clinical practice pattern in management of diabetic macular edema in Japan: survey results of Japanese retinal specialists. Jpn J Ophthalmol. 2017;61:43–50.CrossRefPubMed
13.
Zurück zum Zitat Hirano T, Toriyama Y, Iesato Y, Imai A, Hirabayashi K, Nagaoka T, et al. Effect of leaking perifoveal microaneurysms on resolution of diabetic macular edema treated by combination therapy using anti-vascular endothelial growth factor and short pulse focal/grid laser photocoagulation. Jpn J Ophthalmol. 2017;61:51–60.CrossRefPubMed Hirano T, Toriyama Y, Iesato Y, Imai A, Hirabayashi K, Nagaoka T, et al. Effect of leaking perifoveal microaneurysms on resolution of diabetic macular edema treated by combination therapy using anti-vascular endothelial growth factor and short pulse focal/grid laser photocoagulation. Jpn J Ophthalmol. 2017;61:51–60.CrossRefPubMed
14.
Zurück zum Zitat Browning DJ, Glassman AR, Aiello LP, Beck RW, Brown DM, Fong DS, et al. Relationship between optical coherence tomography-measured central retinal thickness and visual acuity in diabetic macular edema. Ophthalmology. 2007;114:525–36.CrossRefPubMed Browning DJ, Glassman AR, Aiello LP, Beck RW, Brown DM, Fong DS, et al. Relationship between optical coherence tomography-measured central retinal thickness and visual acuity in diabetic macular edema. Ophthalmology. 2007;114:525–36.CrossRefPubMed
15.
Zurück zum Zitat Otani T, Kishi S, Maruyama Y. Patterns of diabetic macular edema with optical coherence tomography. Am J Ophthalmol. 1999;127:688–93.CrossRefPubMed Otani T, Kishi S, Maruyama Y. Patterns of diabetic macular edema with optical coherence tomography. Am J Ophthalmol. 1999;127:688–93.CrossRefPubMed
16.
Zurück zum Zitat Murakami T, Nishijima K, Sakamoto A, Ota M, Horii T, Yoshimura N. Foveal cystoid spaces are associated with enlarged foveal avascular zone and microaneurysms in diabetic macular edema. Ophthalmology. 2011;118:359–67.CrossRefPubMed Murakami T, Nishijima K, Sakamoto A, Ota M, Horii T, Yoshimura N. Foveal cystoid spaces are associated with enlarged foveal avascular zone and microaneurysms in diabetic macular edema. Ophthalmology. 2011;118:359–67.CrossRefPubMed
17.
Zurück zum Zitat Murakami T, Uji A, Ogino K, Unoki N, Horii T, Yoshitake S, et al. Association between perifoveal hyperfluorescence and serous retinal detachment in diabetic macular edema. Ophthalmology. 2013;120:2596–603.CrossRefPubMed Murakami T, Uji A, Ogino K, Unoki N, Horii T, Yoshitake S, et al. Association between perifoveal hyperfluorescence and serous retinal detachment in diabetic macular edema. Ophthalmology. 2013;120:2596–603.CrossRefPubMed
18.
Zurück zum Zitat Sakamoto A, Nishijima K, Kita M, Oh H, Tsujikawa A, Yoshimura N. Association between foveal photoreceptor status and visual acuity after resolution of diabetic macular edema by pars plana vitrectomy. Graefes Arch Clin Exp Ophthalmol. 2009;247:1325–30.CrossRefPubMed Sakamoto A, Nishijima K, Kita M, Oh H, Tsujikawa A, Yoshimura N. Association between foveal photoreceptor status and visual acuity after resolution of diabetic macular edema by pars plana vitrectomy. Graefes Arch Clin Exp Ophthalmol. 2009;247:1325–30.CrossRefPubMed
19.
Zurück zum Zitat Spaide RF, Curcio CA. Anatomical correlates to the bands seen in the outer retina by optical coherence tomography: literature review and model. Retina. 2011;31:1609–19.CrossRefPubMedPubMedCentral Spaide RF, Curcio CA. Anatomical correlates to the bands seen in the outer retina by optical coherence tomography: literature review and model. Retina. 2011;31:1609–19.CrossRefPubMedPubMedCentral
20.
Zurück zum Zitat Murakami T, Nishijima K, Akagi T, Uji A, Horii T, Ueda-Arakawa N, et al. Optical coherence tomographic reflectivity of photoreceptors beneath cystoid spaces in diabetic macular edema. Invest Ophthalmol Vis Sci. 2012;53:1506–11.CrossRefPubMed Murakami T, Nishijima K, Akagi T, Uji A, Horii T, Ueda-Arakawa N, et al. Optical coherence tomographic reflectivity of photoreceptors beneath cystoid spaces in diabetic macular edema. Invest Ophthalmol Vis Sci. 2012;53:1506–11.CrossRefPubMed
21.
Zurück zum Zitat Sun JK, Lin MM, Lammer J, Prager S, Sarangi R, Silva PS, et al. Disorganization of the retinal inner layers as a predictor of visual acuity in eyes with center-involved diabetic macular edema. JAMA Ophthalmol. 2014;132:1309–16.CrossRefPubMed Sun JK, Lin MM, Lammer J, Prager S, Sarangi R, Silva PS, et al. Disorganization of the retinal inner layers as a predictor of visual acuity in eyes with center-involved diabetic macular edema. JAMA Ophthalmol. 2014;132:1309–16.CrossRefPubMed
22.
Zurück zum Zitat Bolz M, Schmidt-Erfurth U, Deak G, Mylonas G, Kriechbaum K, Scholda C. Optical coherence tomographic hyperreflective foci: a morphologic sign of lipid extravasation in diabetic macular edema. Ophthalmology. 2009;116:914–20.CrossRefPubMed Bolz M, Schmidt-Erfurth U, Deak G, Mylonas G, Kriechbaum K, Scholda C. Optical coherence tomographic hyperreflective foci: a morphologic sign of lipid extravasation in diabetic macular edema. Ophthalmology. 2009;116:914–20.CrossRefPubMed
23.
Zurück zum Zitat Horii T, Murakami T, Nishijima K, Akagi T, Uji A, Arakawa N, et al. Relationship between fluorescein pooling and optical coherence tomographic reflectivity of cystoid spaces in diabetic macular edema. Ophthalmology. 2012;119:1047–55.CrossRefPubMed Horii T, Murakami T, Nishijima K, Akagi T, Uji A, Arakawa N, et al. Relationship between fluorescein pooling and optical coherence tomographic reflectivity of cystoid spaces in diabetic macular edema. Ophthalmology. 2012;119:1047–55.CrossRefPubMed
24.
Zurück zum Zitat Horii T, Murakami T, Nishijima K, Sakamoto A, Ota M, Yoshimura N. Optical coherence tomographic characteristics of microaneurysms in diabetic retinopathy. Am J Ophthalmol. 2010;150:840–8.CrossRefPubMed Horii T, Murakami T, Nishijima K, Sakamoto A, Ota M, Yoshimura N. Optical coherence tomographic characteristics of microaneurysms in diabetic retinopathy. Am J Ophthalmol. 2010;150:840–8.CrossRefPubMed
25.
Zurück zum Zitat Otani T, Kishi S. Correlation between optical coherence tomography and fluorescein angiography findings in diabetic macular edema. Ophthalmology. 2007;114:104–7.CrossRefPubMed Otani T, Kishi S. Correlation between optical coherence tomography and fluorescein angiography findings in diabetic macular edema. Ophthalmology. 2007;114:104–7.CrossRefPubMed
26.
Zurück zum Zitat Murakami T, Nishijima K, Sakamoto A, Ota M, Horii T, Yoshimura N. Association of pathomorphology, photoreceptor status, and retinal thickness with visual acuity in diabetic retinopathy. Am J Ophthalmol. 2011;151:310–7.CrossRefPubMed Murakami T, Nishijima K, Sakamoto A, Ota M, Horii T, Yoshimura N. Association of pathomorphology, photoreceptor status, and retinal thickness with visual acuity in diabetic retinopathy. Am J Ophthalmol. 2011;151:310–7.CrossRefPubMed
27.
Zurück zum Zitat Sophie R, Lu N, Campochiaro PA. Predictors of functional and anatomic outcomes in patients with diabetic macular edema treated with ranibizumab. Ophthalmology. 2015;122:1395–401.CrossRefPubMed Sophie R, Lu N, Campochiaro PA. Predictors of functional and anatomic outcomes in patients with diabetic macular edema treated with ranibizumab. Ophthalmology. 2015;122:1395–401.CrossRefPubMed
28.
Zurück zum Zitat Rayess N, Rahimy E, Ying GS, Bagheri N, Ho AC, Regillo CD, et al. Baseline choroidal thickness as a predictor for response to anti-vascular endothelial growth factor therapy in diabetic macular edema. Am J Ophthalmol. 2015;159(85–91):e1–3. Rayess N, Rahimy E, Ying GS, Bagheri N, Ho AC, Regillo CD, et al. Baseline choroidal thickness as a predictor for response to anti-vascular endothelial growth factor therapy in diabetic macular edema. Am J Ophthalmol. 2015;159(85–91):e1–3.
29.
Zurück zum Zitat Kim M, Lee P, Kim Y, Yu SY, Kwak HW. Effect of intravitreal bevacizumab based on optical coherence tomography patterns of diabetic macular edema. Ophthalmologica. 2011;226:138–44.CrossRefPubMed Kim M, Lee P, Kim Y, Yu SY, Kwak HW. Effect of intravitreal bevacizumab based on optical coherence tomography patterns of diabetic macular edema. Ophthalmologica. 2011;226:138–44.CrossRefPubMed
30.
Zurück zum Zitat Roh MI, Kim JH, Kwon OW. Features of optical coherence tomography are predictive of visual outcomes after intravitreal bevacizumab injection for diabetic macular edema. Ophthalmologica. 2010;224:374–80.CrossRefPubMed Roh MI, Kim JH, Kwon OW. Features of optical coherence tomography are predictive of visual outcomes after intravitreal bevacizumab injection for diabetic macular edema. Ophthalmologica. 2010;224:374–80.CrossRefPubMed
31.
Zurück zum Zitat Al Faran A, Mousa A, Al Shamsi H, Al Gaeed A, Ghazi NG. Spectral domain optical coherence tomography predictors of visual outcome in diabetic cystoid macular edema after bevacizumab injection. Retina. 2014;34:1208–15.CrossRefPubMed Al Faran A, Mousa A, Al Shamsi H, Al Gaeed A, Ghazi NG. Spectral domain optical coherence tomography predictors of visual outcome in diabetic cystoid macular edema after bevacizumab injection. Retina. 2014;34:1208–15.CrossRefPubMed
32.
Zurück zum Zitat Querques G, Bux AV, Martinelli D, Iaculli C, Noci ND. Intravitreal pegaptanib sodium (Macugen) for diabetic macular oedema. Acta Ophthalmol. 2009;87:623–30.CrossRefPubMed Querques G, Bux AV, Martinelli D, Iaculli C, Noci ND. Intravitreal pegaptanib sodium (Macugen) for diabetic macular oedema. Acta Ophthalmol. 2009;87:623–30.CrossRefPubMed
33.
Zurück zum Zitat Chung H, Park B, Shin HJ, Kim HC. Correlation of fundus autofluorescence with spectral-domain optical coherence tomography and vision in diabetic macular edema. Ophthalmology. 2012;119:1056–65.CrossRefPubMed Chung H, Park B, Shin HJ, Kim HC. Correlation of fundus autofluorescence with spectral-domain optical coherence tomography and vision in diabetic macular edema. Ophthalmology. 2012;119:1056–65.CrossRefPubMed
34.
Zurück zum Zitat Domalpally A, Ip MS, Ehrlich JS. Effects of intravitreal ranibizumab on retinal hard exudate in diabetic macular edema: findings from the RIDE and RISE phase III clinical trials. Ophthalmology. 2015;122:779–86.CrossRefPubMed Domalpally A, Ip MS, Ehrlich JS. Effects of intravitreal ranibizumab on retinal hard exudate in diabetic macular edema: findings from the RIDE and RISE phase III clinical trials. Ophthalmology. 2015;122:779–86.CrossRefPubMed
35.
Zurück zum Zitat Pemp B, Deak G, Prager S, Mitsch C, Lammer J, Schmidinger G, et al. Distribution of intraretinal exudates in diabetic macular edema during anti-vascular endothelial growth factor therapy observed by spectral domain optical coherence tomography and fundus photography. Retina. 2014;34:2407–15.CrossRefPubMed Pemp B, Deak G, Prager S, Mitsch C, Lammer J, Schmidinger G, et al. Distribution of intraretinal exudates in diabetic macular edema during anti-vascular endothelial growth factor therapy observed by spectral domain optical coherence tomography and fundus photography. Retina. 2014;34:2407–15.CrossRefPubMed
36.
Zurück zum Zitat Bressler SB, Qin H, Beck RW, Chalam KV, Kim JE, Melia M, et al. Factors associated with changes in visual acuity and central subfield thickness at 1 year after treatment for diabetic macular edema with ranibizumab. Arch Ophthalmol. 2012;130:1153–61.CrossRefPubMedPubMedCentral Bressler SB, Qin H, Beck RW, Chalam KV, Kim JE, Melia M, et al. Factors associated with changes in visual acuity and central subfield thickness at 1 year after treatment for diabetic macular edema with ranibizumab. Arch Ophthalmol. 2012;130:1153–61.CrossRefPubMedPubMedCentral
37.
Zurück zum Zitat Framme C, Schweizer P, Imesch M, Wolf S, Wolf-Schnurrbusch U. Behavior of SD-OCT-detected hyperreflective foci in the retina of anti-VEGF-treated patients with diabetic macular edema. Invest Ophthalmol Vis Sci. 2012;53:5814–8.CrossRefPubMed Framme C, Schweizer P, Imesch M, Wolf S, Wolf-Schnurrbusch U. Behavior of SD-OCT-detected hyperreflective foci in the retina of anti-VEGF-treated patients with diabetic macular edema. Invest Ophthalmol Vis Sci. 2012;53:5814–8.CrossRefPubMed
38.
Zurück zum Zitat Aveleira CA, Lin CM, Abcouwer SF, Ambrosio AF, Antonetti DA. TNF-alpha signals through PKCzeta/NF-kappaB to alter the tight junction complex and increase retinal endothelial cell permeability. Diabetes. 2010;59:2872–82.CrossRefPubMedPubMedCentral Aveleira CA, Lin CM, Abcouwer SF, Ambrosio AF, Antonetti DA. TNF-alpha signals through PKCzeta/NF-kappaB to alter the tight junction complex and increase retinal endothelial cell permeability. Diabetes. 2010;59:2872–82.CrossRefPubMedPubMedCentral
39.
Zurück zum Zitat Joussen AM, Poulaki V, Mitsiades N, Kirchhof B, Koizumi K, Dohmen S, et al. Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression. FASEB J. 2002;16:438–40.CrossRefPubMed Joussen AM, Poulaki V, Mitsiades N, Kirchhof B, Koizumi K, Dohmen S, et al. Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression. FASEB J. 2002;16:438–40.CrossRefPubMed
40.
Zurück zum Zitat Joussen AM, Poulaki V, Mitsiades N, Cai WY, Suzuma I, Pak J, et al. Suppression of Fas-FasL-induced endothelial cell apoptosis prevents diabetic blood-retinal barrier breakdown in a model of streptozotocin-induced diabetes. FASEB J. 2003;17:76–8.CrossRefPubMed Joussen AM, Poulaki V, Mitsiades N, Cai WY, Suzuma I, Pak J, et al. Suppression of Fas-FasL-induced endothelial cell apoptosis prevents diabetic blood-retinal barrier breakdown in a model of streptozotocin-induced diabetes. FASEB J. 2003;17:76–8.CrossRefPubMed
Metadaten
Titel
Association between characteristics of foveal cystoid spaces and short-term responsiveness to ranibizumab for diabetic macular edema
verfasst von
Tomoaki Murakami
Kiyoshi Suzuma
Akihito Uji
Shin Yoshitake
Yoko Dodo
Masahiro Fujimoto
Tatsuya Yoshitake
Yuko Miwa
Nagahisa Yoshimura
Publikationsdatum
19.02.2018
Verlag
Springer Japan
Erschienen in
Japanese Journal of Ophthalmology / Ausgabe 3/2018
Print ISSN: 0021-5155
Elektronische ISSN: 1613-2246
DOI
https://doi.org/10.1007/s10384-018-0575-8

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