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Article ; Online: Longer Interscan Times in OCT Angiography Detect Slower Capillary Flow in Diabetic Retinopathy.

Kaizu, Yoshihiro / Nakao, Shintaro / Soda, Tomomi / Horie, Juun / Wada, Iori / Yamaguchi, Muneo / Takeda, Atsunobu / Sonoda, Koh-Hei

Ophthalmology science

2022 Volume 2, Issue 3, Page(s) 100181

Abstract: Purpose: To investigate the detection of slower retinal capillary blood flow using commercial OCT angiography (OCTA) with a longer interscan time in diabetic retinopathy (DR).: Design: Observational, prospective, cross-sectional study.: ... ...

Abstract	Purpose: To investigate the detection of slower retinal capillary blood flow using commercial OCT angiography (OCTA) with a longer interscan time in diabetic retinopathy (DR). Design: Observational, prospective, cross-sectional study. Participants: A total of 62 eyes from 39 subjects with diabetes mellitus and 10 eyes from 9 healthy subjects. Methods: Commercial spectral domain-OCT was used to obtain 3 × 3-mm fovea-centered OCTA images of all eyes with 3 different interscan times (4.3, 5.7, and 8.6 ms). For each interscan time, OCTA imaging was performed 5 consecutive times, and a ×5 averaged image was obtained. Capillary flow density and visualization of retinal capillaries in the superficial and deep capillary plexuses (SCPs and DCPs, respectively) were compared between the 3 averaged images from the 3 different interscan times. Main outcome measures: Capillary flow density and visualization of foveal capillaries in 3 images with different interscan times. Results: Forty-five eyes of 34 patients were analyzed. There was no significant difference in the flow density of the SCP and DCP between the 3 images with different interscan times in all the DR stages. Some capillaries including microaneurysms that could not be observed at 4.3 ms could be observed at 5.7 or 8.6 ms. There were significantly more capillaries with difference points between the 3 images in the group with DR than in the group without DR ( Conclusions: OCTA with longer interscan times revealed slower flow points in capillaries and more accurate visualization and morphology of microaneurysms in DR.
Language	English
Publishing date	2022-06-13
Publishing country	Netherlands
Document type	Journal Article
ISSN	2666-9145
ISSN (online)	2666-9145
DOI	10.1016/j.xops.2022.100181
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Article ; Online: Morphology and fluorescein leakage in diabetic retinal microaneurysms: a study using multiple en face OCT angiography image averaging.

Fukuda, Yosuke / Nakao, Shintaro / Kaizu, Yoshihiro / Arima, Mitsuru / Shimokawa, Sakurako / Wada, Iori / Yamaguchi, Muneo / Takeda, Atsunobu / Sonoda, Koh-Hei

Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie

2022 Volume 260, Issue 11, Page(s) 3517–3523

Abstract: Purpose: To investigate the relevance of microaneurysm morphology in optical coherence tomography angiography (OCTA) image averaging and fluorescein leakage in diabetic retinopathy (DR).: Methods: In 38 consecutive patients with DR, ten consecutive 3- ...

Abstract	Purpose: To investigate the relevance of microaneurysm morphology in optical coherence tomography angiography (OCTA) image averaging and fluorescein leakage in diabetic retinopathy (DR). Methods: In 38 consecutive patients with DR, ten consecutive 3- × 3-mm fovea-centered OCTA (HS100, Canon Inc., Tokyo, Japan) and fluorescein angiography (FA) were performed, and averaged OCTA images were created based on the 10 images. After detecting all microaneurysms in FA images, the morphology was classified into four types (focal bulge, saccular/pedunculated, fusiform, and mixed) using averaged OCTA images. The correlation between microaneurysm leakage in FA, retinopathy stage, and microaneurysm morphology was estimated. Results: Thirty-eight eyes (50.0%) of the 33 patients were available for analysis, and 370 (63.5%) of the 583 FA-detected microaneurysms were morphologically classifiable (focal bulge, 46; saccular/pedunculated, 143; fusiform, 29; and mixed, 152) in OCTA. There was a significant correlation between stage and percentage of microaneurysm morphology and between morphology and the presence of leakage (P < 0.0001 and P < 0.01, respectively). The proportion of focal bulges decreased with stage progression, while the other three types increased with stage progression. The percentage of FA leakage for focal bulge, saccular/pedunculated, fusiform, and mixed was 41.3%, 66.4%, 82.8%, and 66.4%, respectively, and the fusiform type showed significant FA leakage. Conclusion: Microaneurysm morphology is correlated with the DR stage and FA leakage. Microaneurysm morphology recognition using OCTA image averaging may be useful for the clinical evaluation of DR.
MeSH term(s)	Humans ; Diabetic Retinopathy/complications ; Diabetic Retinopathy/diagnosis ; Microaneurysm/diagnosis ; Microaneurysm/etiology ; Tomography, Optical Coherence/methods ; Retinal Vessels ; Visual Acuity ; Fluorescein Angiography/methods ; Fovea Centralis ; Fluoresceins ; Diabetes Mellitus
Chemical Substances	Fluoresceins
Language	English
Publishing date	2022-06-04
Publishing country	Germany
Document type	Journal Article
ZDB-ID	8435-9
ISSN	1435-702X ; 0721-832X
ISSN (online)	1435-702X
ISSN	0721-832X
DOI	10.1007/s00417-022-05713-7
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Article ; Online: Diabetic vascular hyperpermeability: optical coherence tomography angiography and functional loss assessments of relationships among retinal vasculature changes.

Arima, Mitsuru / Nakao, Shintaro / Kaizu, Yoshihiro / Wada, Iori / Yamaguchi, Muneo / Fujiwara, Kohta / Akiyama, Masato / Stitt, Alan W / Sonoda, Koh-Hei

Scientific reports

2021 Volume 11, Issue 1, Page(s) 4185

Abstract: Our study assessed the influence of vascular permeability on vascular flow density (FD)-correlated retinal sensitivity (RS) in DR. In this cross-sectional, prospective, consecutive study, RS in the extrafoveal macula of DR patient was measured by ... ...

Abstract	Our study assessed the influence of vascular permeability on vascular flow density (FD)-correlated retinal sensitivity (RS) in DR. In this cross-sectional, prospective, consecutive study, RS in the extrafoveal macula of DR patient was measured by microperimetry. FD was measured in the total, superficial, and deep capillary plexus layers (TCP, SCP, and DCP) by optical coherence tomography angiography. All measurement points were classified into four categories according to intensity of fluorescein leakage and FD, and the RS reduction was compared. A stratified analysis by retinal thickness (RT) was also performed. Fourteen eyes (14 patients) were enrolled. FDs at 207 RS measurement points were analyzable. For TCP, SCP and DCP, the leakage did not decrease RS at points where FD was maintained. The greater the leakage, the smaller the RS reduction at points with low FD in TCP (P = .020). Points with high leakage showed a significant smaller RS reduction than points with low leakage (P = .001 for TCP, P = .040 for SCP, and P = .046 for DCP) only in areas with low RT and low FD. Our results suggested that vascular hyperpermeability may inhibit the RS reduction in the non-edematous ischemic diabetic retina.
MeSH term(s)	Cross-Sectional Studies ; Diabetes Mellitus/pathology ; Diabetic Retinopathy/pathology ; Female ; Fluorescein Angiography/methods ; Humans ; Macula Lutea/pathology ; Male ; Middle Aged ; Prospective Studies ; Retinal Vessels/pathology ; Tomography, Optical Coherence/methods
Language	English
Publishing date	2021-02-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-83334-6
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Article ; Online: VOLUMETRIC THREE-DIMENSIONAL OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF RETINAL NEOVASCULARIZATION IN PROLIFERATIVE DIABETIC RETINOPATHY.

Nakao, Shintaro / Kaizu, Yoshihiro / Horie, Juun / Wada, Iori / Arima, Mitsuru / Fukuda, Yosuke / Ishikawa, Keijiro / Sonoda, Koh-Hei

Retinal cases & brief reports

2021 Volume 17, Issue 3, Page(s) 315–320

Abstract: Purpose: To evaluate structural and angiographic neovascularization in patients with proliferative diabetic retinopathy using volumetric three-dimensional optical coherence tomography angiography (OCTA).: Methods: This prospective, observational ... ...

Abstract	Purpose: To evaluate structural and angiographic neovascularization in patients with proliferative diabetic retinopathy using volumetric three-dimensional optical coherence tomography angiography (OCTA). Methods: This prospective, observational cross-sectional study included 29 eyes of 27 patients with proliferative diabetic retinopathy. The angiogenic structure, feeding vessel (epicenter), flow volume, and flow volume density of the neovasculatures were evaluated using three-dimensional OCTA imaging. The flow area and the flow area density were also measured using en face OCTA imaging. Results: Sites of neovascularization were imaged successfully in 17 of the 29 eyes (58.6%). Three proposed types of neovascularization were identified on the basis of structural features seen on the three-dimensional OCTA images. Neovascularization of the adhesion type (9 of 17, 52.9%) adhered to the retinal vasculature. Those of the traction type (5 of 17, 29.4%) were partially separated from the retinal vascular plexus. Those of the mushroom type (3 of 17, 17.6%) were connected to the retinal vasculature by several epicenters. There was a significant difference between highly leaky (active) and faintly leaky (inactive) neovascularization for flow volume density, but not for flow area, flow volume, or flow area density ( P = 0.01, 0.9, 0.6, and 0.1, respectively). Conclusion: Volumetric three-dimensional OCTA revealed three types of neovascularization in proliferative diabetic retinopathy and may be useful for assessing neovascular activity and planning vitrectomies.
MeSH term(s)	Humans ; Retinal Neovascularization ; Diabetic Retinopathy ; Fluorescein Angiography/methods ; Tomography, Optical Coherence/methods ; Cross-Sectional Studies ; Prospective Studies ; Retinal Vessels ; Diabetes Mellitus
Language	English
Publishing date	2021-07-25
Publishing country	United States
Document type	Observational Study ; Journal Article
ISSN	1937-1578
ISSN (online)	1937-1578
DOI	10.1097/ICB.0000000000001183
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Article ; Online: Publisher Correction: Diabetic vascular hyperpermeability: optical coherence tomography angiography and functional loss assessments of relationships among retinal vasculature changes.

Arima, Mitsuru / Nakao, Shintaro / Kaizu, Yoshihiro / Wada, Iori / Yamaguchi, Muneo / Fujiwara, Kohta / Akiyama, Masato / Stitt, Alan W / Sonoda, Koh-Hei

Scientific reports

2021 Volume 11, Issue 1, Page(s) 12344

Language	English
Publishing date	2021-06-07
Publishing country	England
Document type	Published Erratum
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-91789-w
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Article ; Online: Retinal VEGF-A Overexpression Is Not Sufficient to Induce Lymphangiogenesis Regardless of VEGF-C Upregulation and Lyve1+ Macrophage Infiltration.

Wada, Iori / Nakao, Shintaro / Yamaguchi, Muneo / Kaizu, Yoshihiro / Arima, Mitsuru / Sawa, Shinichiro / Sonoda, Koh-Hei

Investigative ophthalmology & visual science

2021 Volume 62, Issue 13, Page(s) 17

Abstract: Purpose: No lymphatic vessels have been identified in the retina. This study investigated whether pathological VEGF-A-overexpressing diabetic retina causes lymphangiogenesis.: Methods: Three genetic mouse models of diabetic retinopathy (DR) (Akita [ ... ...

Abstract	Purpose: No lymphatic vessels have been identified in the retina. This study investigated whether pathological VEGF-A-overexpressing diabetic retina causes lymphangiogenesis. Methods: Three genetic mouse models of diabetic retinopathy (DR) (Akita [Ins2+/-], Kimba [vegfa+/+], and Akimba [Akita × Kimba] mice) were used. Retinas were examined by fundus photography, fluorescence angiography (FA), and immunostaining to detect lymphangiogenesis or angiogenesis. Lyve1-GFP (Lyve1EGFP/Cre) mice were used to examine Lyve1-expressing cells by immunostaining. Lymphatic-related factors were investigated in mouse retina and vitreous fluid from proliferative diabetic retinopathy (PDR) patients by RT-PCR and ELISA, respectively. Aged Kimba and Akimba mice were used to examine the retinal phenotype at the late phase of VEGF overexpression. Results: FA and immunostaining showed retinal neovascularization in Kimba and Akimba mice but not wild-type and Akita mice. Immunohistochemistry showed that lymphangiogenesis was not present in the retinas of Akita, Kimba, or Akimba mice despite the significant upregulation of lymphatic-related factors (Lyve1, podoplanin, VEGF-A, VEGF-C, VEGF-D, VEGFR2, and VEGFR3) in the retinas of Kimba and Akimba mice by RT-PCR (P < 0.005). Furthermore, lymphangiogenesis was not present in aged Kimba or Akimba mice. Significantly increased numbers of Lyve1-positive cells present in the retinas of Kimba and Akimba mice, especially in the peripheral areas, were CD11b positive, indicating a macrophage population (P < 0.005). VEGF-C in PDR vitreous with vitreous hemorrhage (VH) was higher than in PDR without VH or a macular hole. Conclusions: Retinal VEGF-A overexpression did not cause typical lymphangiogenesis despite upregulated lymphatic-related factors and significant Lyve1-positive macrophage infiltration.
MeSH term(s)	Animals ; Diabetes Mellitus, Experimental ; Diabetic Retinopathy/diagnostic imaging ; Diabetic Retinopathy/genetics ; Diabetic Retinopathy/metabolism ; Fluorescein Angiography/methods ; Gene Expression Regulation ; Lymphangiogenesis/genetics ; Lymphatic Vessels/metabolism ; Lymphatic Vessels/pathology ; Mice, Inbred C57BL ; RNA/genetics ; Retina/metabolism ; Retina/pathology ; Up-Regulation ; Vascular Endothelial Growth Factor C/biosynthesis ; Vascular Endothelial Growth Factor C/genetics ; Vesicular Transport Proteins/biosynthesis ; Vesicular Transport Proteins/genetics ; Mice
Chemical Substances	LYVE1 protein, mouse ; Vascular Endothelial Growth Factor C ; Vesicular Transport Proteins ; vascular endothelial growth factor C, mouse ; RNA (63231-63-0)
Language	English
Publishing date	2021-10-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	391794-0
ISSN	1552-5783 ; 0146-0404
ISSN (online)	1552-5783
ISSN	0146-0404
DOI	10.1167/iovs.62.13.17
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Article ; Online: Branch retinal artery occlusion in the untreated contralateral eye following aflibercept injections during heparin treatment: Possible contribution of a heparin-induced thrombocytopenia-like condition.

Nakao, Shintaro / Yoshimitsu, Makoto / Kaizu, Yoshihiro / Wada, Iori / Yamaguchi, Muneo / Sonoda, Koh-Hei

American journal of ophthalmology case reports

2019 Volume 16, Page(s) 100549

Abstract: Purpose: In this study, we report a case of branch retinal artery occlusion (BRAO) in the contralateral eye the day after aflibercept treatment during systemic heparin administration.: Observations: A 63-year-old woman with diabetic macular edema ... ...

Abstract	Purpose: In this study, we report a case of branch retinal artery occlusion (BRAO) in the contralateral eye the day after aflibercept treatment during systemic heparin administration. Observations: A 63-year-old woman with diabetic macular edema underwent repeated intravitreal injection of anti-VEGF drugs (0.5mg ranibizumab or 2mg aflibercept) for her left eye. The day after intravitreal injection of aflibercept, she presented with sudden painless blurred vision that was limited to the inferior visual field defect in the contralateral eye (right eye) during hemodialysis with the anti-coagulant heparin. Optical coherence tomography angiography (OCTA) showed decreased artery perfusion and the patient was diagnosed with contralateral BRAO. Conclusions: Previous
Language	English
Publishing date	2019-08-28
Publishing country	United States
Document type	Case Reports
ISSN	2451-9936
ISSN (online)	2451-9936
DOI	10.1016/j.ajoc.2019.100549
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Article ; Online: Hyperreflective Membrane at the Vitreoretinal Interface in Diabetic Macular Edema: A Finding in Ultra-High-Resolution Optical Coherence Tomography.

Wada, Iori / Nakao, Shintaro / Arima, Mitsuru / Ishikawa, Keijiro / Yamaguchi, Muneo / Kaizu, Yoshihiro / Sekiryu, Haruka / Mori, Kenichiro / Kiyohara, Kohei / Takeda, Atsunobu / Ishibashi, Tatsuro / Sadda, SriniVas R / Sonoda, Koh-Hei

Translational vision science & technology

2022 Volume 11, Issue 9, Page(s) 21

Abstract: Purpose: Detecting subtle vitreoretinal interface (VRI) findings, such as a posterior hyaloid membrane, is difficult with conventional retinal imaging. We compared ultra-high-resolution spectral domain optical coherence tomography (UHR-SD-OCT) with ... ...

Abstract	Purpose: Detecting subtle vitreoretinal interface (VRI) findings, such as a posterior hyaloid membrane, is difficult with conventional retinal imaging. We compared ultra-high-resolution spectral domain optical coherence tomography (UHR-SD-OCT) with standard-resolution OCT (SD-OCT) for the imaging of VRI abnormalities in diabetic retinopathy (DR). Methods: This prospective cross-sectional study included 113 consecutive patients (91 patients with diabetes and 22 healthy controls). The VRI was evaluated, and the results were compared between the conventional SD-OCT and UHR-SD-OCT images. VRI findings were also investigated before and after internal limiting membrane peeling during vitrectomy for proliferative DR. Results: A total of 159 eyes (87.4%) of 91 patients with diabetes were analyzed. UHR-SD-OCT could detect a hyperreflective layer at the VRI, in which en face OCT showed a membrane-like structure, termed the hyperreflective membrane (HRMe). The preoperative HRMe could not be detected in all patients with proliferative DR who underwent internal limiting membrane peeling during vitrectomy. Although the HRMe did not correlate with the DR stage, eyes with diabetic macular edema (DME) (64.5%) showed a significant HRMe with UHR-SD-OCT more frequently than those without DME (35.8%) (P = 0.005). Conclusions: UHR-SD-OCT can detect the HRMe at the VRI in DR eyes, particularly in eyes with DME. The HRMe may present a thickened posterior hyaloid membrane that contributes to DME development. Translational relevance: UHR-SD-OCT detects slight changes in the VRI in DR eyes. In the future, it may help to elucidate the mechanism of DME formation.
MeSH term(s)	Cross-Sectional Studies ; Diabetes Mellitus ; Diabetic Retinopathy/diagnosis ; Diabetic Retinopathy/diagnostic imaging ; Humans ; Macular Edema/diagnostic imaging ; Prospective Studies ; Retrospective Studies ; Tomography, Optical Coherence/methods ; Visual Acuity
Language	English
Publishing date	2022-09-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2674602-5
ISSN	2164-2591 ; 2164-2591
ISSN (online)	2164-2591
ISSN	2164-2591
DOI	10.1167/tvst.11.9.21
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Article ; Online: Eye Explorer: A robotic endoscope holder for eye surgery.

Zhou, Dongbo / Kimura, Shintaro / Takeyama, Hayato / Haraguchi, Daisuke / Kaizu, Yoshihiro / Nakao, Shintaro / Sonoda, Koh-Hei / Tadano, Kotaro

The international journal of medical robotics + computer assisted surgery : MRCAS

2020 Volume 17, Issue 1, Page(s) 1–13

Abstract: Background: Holding endoscopes by hand when performing eye surgery reduces the dexterity of the surgeon.: Methods: A robotic endoscope holder called "Eye Explorer" is proposed to hold the endoscope and free the surgeon's hand.: Results: This ... ...

Abstract	Background: Holding endoscopes by hand when performing eye surgery reduces the dexterity of the surgeon. Methods: A robotic endoscope holder called "Eye Explorer" is proposed to hold the endoscope and free the surgeon's hand. Results: This device satisfies the engineering and clinical requirements of eye surgery. The force for manual operation is less than 0.5 N. The observable ranges inside the patient's eye considering horizontal and vertical perspectives are 118° and 97°, and the motion of the holder does not interfere with the surgeon's hand and other surgical devices. The self-weight compensation can prevent the endoscope from falling when extra supporting force is released. When comparing the external force exerted on the eye by the Eye Explorer with that in case of manual operation, a decrease of more than 15% can be observed. Moreover, the consumption time of endoscope view adjustment using the Eye Explorer and manual operation does not significantly differ. Conclusion: The Eye Explorer allows dual-hand operation, facilitating a successful endoscopic eye surgery.
MeSH term(s)	Endoscopes ; Endoscopy ; Equipment Design ; Humans ; Ophthalmologic Surgical Procedures ; Robotic Surgical Procedures ; Robotics
Language	English
Publishing date	2020-10-10
Publishing country	England
Document type	Journal Article
ZDB-ID	2151860-9
ISSN	1478-596X ; 1478-5951
ISSN (online)	1478-596X
ISSN	1478-5951
DOI	10.1002/rcs.2177
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Article ; Online: Identifying Hyperreflective Foci in Diabetic Retinopathy via VEGF-Induced Local Self-Renewal of CX3CR1+ Vitreous Resident Macrophages.

Yamaguchi, Muneo / Nakao, Shintaro / Wada, Iori / Matoba, Tetsuya / Arima, Mitsuru / Kaizu, Yoshihiro / Shirane, Mariko / Ishikawa, Keijiro / Nakama, Takahito / Murakami, Yusuke / Mizuochi, Masaharu / Shiraishi, Wataru / Yamasaki, Ryo / Hisatomi, Toshio / Ishibashi, Tatsuro / Shibuya, Masabumi / Stitt, Alan W / Sonoda, Koh-Hei

Diabetes

2022 Volume 71, Issue 12, Page(s) 2685–2701

Abstract: Intraretinal hyperreflective foci (HRF) are significant biomarkers for diabetic macular edema. However, HRF at the vitreoretinal interface (VRI) have not been examined in diabetic retinopathy (DR). A prospective observational clinical study with 162 ... ...

Abstract	Intraretinal hyperreflective foci (HRF) are significant biomarkers for diabetic macular edema. However, HRF at the vitreoretinal interface (VRI) have not been examined in diabetic retinopathy (DR). A prospective observational clinical study with 162 consecutive eyes using OCT imaging showed significantly increased HRF at the VRI during DR progression (P < 0.01), which was reversed by anti-vascular endothelial growth factor (VEGF) therapy. F4/80+ macrophages increased significantly at the VRI in Kimba (vegfa+/+) or Akimba (Akita × Kimba) mice (both P < 0.01), but not in diabetic Akita (Ins2+/-) mice, indicating macrophage activation was modulated by elevated VEGF rather than the diabetic milieu. Macrophage depletion significantly reduced HRF at the VRI (P < 0.01). Furthermore, BrdU administration in Ccr2rfp/+Cx3cr1gfp/+vegfa+/- mice identified a significant contribution of M2-like tissue-resident macrophages (TRMs) at the VRI. Ki-67+ and CD11b+ cells were observed in preretinal tissues of DR patients, while exposure of vitreal macrophages to vitreous derived from PDR patients induced a significant proliferation response in vitro (P < 0.01). Taken together, the evidence suggests that VEGF drives a local proliferation of vitreous resident macrophages (VRMs) at the VRI during DR. This phenomenon helps to explain the derivation and disease-relevance of the HRF lesions observed through OCT imaging in patients.
MeSH term(s)	Mice ; Animals ; Diabetic Retinopathy/metabolism ; Macular Edema ; Vascular Endothelial Growth Factor A ; Macrophages/metabolism ; Prospective Studies ; Tomography, Optical Coherence ; Diabetes Mellitus/pathology ; CX3C Chemokine Receptor 1/genetics
Chemical Substances	Vascular Endothelial Growth Factor A ; Cx3cr1 protein, mouse ; CX3C Chemokine Receptor 1
Language	English
Publishing date	2022-10-18
Publishing country	United States
Document type	Observational Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db21-0247
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