bluuebunny/crossref_metadata_2025_split huggingface dataset:
286-OR: Biomedical Predictors of Cognitive Decline in Older Participants with T1DM: Longitudinal Follow-Up of the DCCT/EDIC Cohort
Authors: JACOBSON ALAN M. , RYAN CHRISTOPHER M. , BRAFFETT BARBARA H. , GUBITOSI-KLUG ROSE , LORENZI GAYLE M. , LUCHSINGER JOSE A. , TRAPANI VICTORIA R. , BEBU IONUT , CHAYTOR NAOMI , HITT SUSAN M. , FARRELL KALEIGH , LACHIN JOHN M. 
Published: June 2020

DCCT/EDIC participants have been followed for an average of 32 years (N=1,054; mean age 60±7 years; duration T1DM 38±5 years). To evaluate cognitive function in T1DM, mental efficiency and memory were assessed five times during the study. Standardized z-scores were calculated relative to the DCCT baseline evaluation and averaged to obtain three summary domain scores (immediate recall, delayed recall, mental efficiency). Generalized linear mixed models were used. In 2018, mean HbA1c levels were 7.9±0.9% and 46% of participants had experienced ≥1 hypoglycemic coma/seizure. Adjusted for age, sex, and education, cognition declined over time (p&lt;0.0001 each domain). In multivariable analysis, higher mean HbA1c (β±SE, -0.105±0.017 per 1%, p&lt;0.0001), higher mean systolic blood pressure (-0.083±0.013 per 5 mmHg, p&lt;0.0001), and history of coma/seizure (-0.175±0.041 ≥1 vs. none, p&lt;0.0001) were independently associated with declining mental efficiency. Decreased mental efficiency was also associated with microalbuminuria (AER ≥30 mg/hr), lower levels of HDL cholesterol, and higher daily insulin dose (u/kg/day) (each p&lt;0.0001). Biomedical predictors did not influence recall. These findings demonstrate the effects of increasing age, glycemic excursions (chronic hyperglycemia and clinically-significant hypoglycemia), and blood pressure on mental efficiency.

Disclosure
A.M. Jacobson: None. C.M. Ryan: None. B.H. Braffett: None. R. Gubitosi-Klug: None. G.M. Lorenzi: None. J.A. Luchsinger: Consultant; Self; vTv Therapeutics. V.R. Trapani: None. I. Bebu: None. N. Chaytor: Consultant; Self; Eli Lilly and Company. S.M. Hitt: None. K. Farrell: Stock/Shareholder; Spouse/Partner; Dexcom, Inc., Tandem Diabetes Care. J.M. Lachin: Board Member; Self; Tolerion, Inc.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases
287-OR: TCR/HLA Humanized Mice Reveal Reduced Tolerance and Increased Immunogenicity of Posttranslationally Modified GAD65 Epitope
Authors: JING YI , KONG YUELIN , MCGINTY JOHN , BLAHNIK-FAGAN GABRIELE , BETTINI MATTHEW , JAMES EDDIE A. , BETTINI MARIA 
Published: June 2020

T cells specific for post-translationally modified (PTM) islet antigens have been implicated as critical players in the development of type 1 diabetes. T cells reactive to the deamidated version of glutamic acid decarboxylase 65 (GAD65) 115-127 epitope accumulate in peripheral blood of patients as they progress to disease. However, knowledge regarding the development, activation, differentiation and islet recruitment of PTM reactive T cells is limited. Using retroviral gene delivery, we have developed a humanized TCR/HLA mouse model to assess the in vivo function of human TCRs reactive to either the wild type (GADWT) or the deamidated (GAD120E) GAD65115-127 epitope. Both TCRs supported efficient thymic selection; however, fewer regulatory T cells developed in mice expressing the PTM reactive TCR, which was partially rescued by the thymic delivery of GAD120E peptide. Immunization of immune sufficient polyclonal DR4.NOD mice with GAD120E/CFA elicited a stronger response compared to GADWT/CFA, confirming that tolerance to the wild type autoantigen is more robust. Interestingly, while islet infiltration in GAD120E single TCR mice was dependent on priming with the cognate PTM peptide, GADWT-TCR T cells could be induced to infiltrate islets after priming with either GADWT or GAD120E peptide, despite the vastly different functional affinity (EC50, GADWT: 0.047μM vs. GAD120E: ≥1.4μM). These findings suggest that the development and expansion of GAD65 PTM reactive CD4+ T cells are less restricted in peripheral lymphoid organs, but their recruitment to the tissue site is dependent on the availability of PTM antigen.

Disclosure
Y. Jing: None. Y. Kong: None. J. McGinty: None. G. Blahnik-Fagan: None. M. Bettini: None. E.A. James: None. M. Bettini: None.

Funding
National Institutes of Health (R01AI125301)
289-OR: JAK Inhibitors Block Interferon and Common Gamma Chain Cytokine Signaling to Reverse Diabetes in NOD Mice
Authors: JHALA GAURANG , GE TINGTING , KRISHNAMURTHY BALASUBRAMANIAN , KAY THOMAS , THOMAS HELEN E. 
Published: June 2020

Cytokines that signal through the JAK-STAT pathway, such as interferon-γ (IFN-γ) and common γ chain cytokines, play an important role in facilitating the destruction of insulin-secreting β cells by CD8+ T cells in type 1 diabetes. We previously showed that inhibiting JAK1/JAK2 reversed autoimmune insulitis in non-obese diabetic (NOD) mice and also blocked IFN-γ mediated MHC class I upregulation on β cells. Blocking interferons on their own did not prevent diabetes in knockout NOD mice, so we tested whether JAK inhibitor action on signaling downstream of common γ chain family cytokines, including IL-2, IL-21, IL-7 and IL-15, may also affect progression of diabetes in NOD mice. Common γ chain cytokines activate JAK1 and JAK3 to regulate T cell proliferation. We compared JAK1-selective inhibitors with our previous data with JAK1/JAK2 inhibition. JAK1-selective inhibitors reduced IL-21, IL-2 and IL-7 signaling in T cells (p&lt;0.05) and IFN-γ signaling in β cells, but did not affect GM-CSF signaling in granulocytes. When given in vivo to NOD mice, JAK1-selective inhibitors reduced CD8+ T cell proliferation (Ki-67) in islets, reduced immune cell infiltration into islets and prevented MHC class I upregulation on β cells as measured by flow cytometry. Newly diagnosed diabetes was reversed in 94% NOD mice treated twice daily with JAK1-selective inhibitors.
Our results indicate that JAK inhibitors block common γ chain cytokines in lymphocytes and interferons in lymphocytes and β cells and are thus more effective against diabetes pathogenesis than IFNγ receptor deficiency alone. Our studies pave the way for use of this class of drug in clinical trials for type 1 diabetes.

Disclosure
G. Jhala: None. T. Ge: None. B. Krishnamurthy: None. T. Kay: None. H.E. Thomas: None.

Funding
National Health and Medical Research Council of Australia (GNT1145507); JDRF (1-SRA-2018-599-S-B)
298-OR: Disruption of Multiple Cell-Autonomous Protein Phosphorylation Networks Underlies Muscle Insulin Resistance in Type 2 Diabetes
Authors: BATISTA THIAGO M. , ALBRECHTSEN NICOLAI J. WEWER , ZIERATH JULEEN R. , MANN MATTHIAS , KAHN C. RONALD 
Published: June 2020

Skeletal muscle insulin resistance is the earliest defect in type 2 diabetes (T2D), however, whether this represents a cell-autonomous defect or is secondary to changes in hormones and other circulating factors in vivo is unclear. To identify primary drivers of skeletal muscle insulin resistance in T2D without interference of these systemic factors, we have developed a “disease-in-a-dish” model by differentiating induced pluripotent stem cells (iPSCs) from T2D patients and controls into skeletal myoblasts (iMyos) and studied their function in vitro (n=8 subjects per group). We find that T2D iMyos retain multiple features of in vivo insulin resistance including altered insulin signaling downstream of the IRS/AKT pathway, impaired insulin-stimulated glucose uptake, and reduced mitochondrial oxidation. More importantly, using global phosphoproteomics we identify nearly 1,000 phosphorylation sites that were significantly increased or decreased (FDR &lt; 0.05) by T2D status. While many of the observed signaling defects in T2D iMyos occurred inside the classical insulin signaling pathway and included dysregulation of Akt, mTOR and forkhead box transcription factors, over 85% of these changes occurred in basal protein phosphorylation. These included phosphorylation of proteins in many pathways not typically involved in insulin resistance, such as mRNA splicing and processing, gene transcription, chromatin remodeling and cytoskeleton dynamics. Motif analysis revealed enrichment of a multiplicity of kinases including ROCK, mTOR/S6K and PKCs with potential targets involved in insulin action, cytoskeleton and cell cycle, without changes in total protein content. This broad dysregulated phosphorylation network reveals a new dimension in the complexity of the cell-autonomous mechanisms underlying insulin resistance in T2D, as well as new targets for therapy or prevention of the disease.

Disclosure
T.M. Batista: None. N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S, Novo Nordisk Foundation. Speaker’s Bureau; Self; Merck Sharp & Dohme Corp. J.R. Zierath: None. M. Mann: None. C. Kahn: Advisory Panel; Self; ERX Pharmaceuticals, Kaleido Biosciences. Consultant; Self; AntriaBio, Flagship Pioneering, Sana-Cobalt.

Funding
National Institutes of Health (R01DK031036, R01DK033201); Swedish Research Council (2015-00165); Novo Nordisk Foundation (NNF18CC0034900)
302-OR: ADA Presidents’ Select Abstract: The Balance of Vascular Tone in the Afferent (RA) and Efferent (RE) Arterioles Associates with Diabetic Kidney Lesions and Predicts Progression to End Stage Kidney Disease (ESKD) in Type 2 Diabetes (T2D)
Authors: SAULNIER PIERRE-JEAN , LOOKER HELEN C. , MAUER MICHAEL , NELSON ROBERT G. , BJORNSTAD PETTER 
Published: June 2020

The balance of RA and RE, a major determinant of intraglomerular pressure (P&lt;glo), may be important in the initiation and progression of diabetic kidney disease (DKD). Although RA and RE are not directly measurable in humans these parameters can be estimated by the Gomez equation using measures of whole-kidney GFR and renal plasma flow (RPF), mean arterial pressure (MAP), hematocrit, and plasma oncotic pressure. We examined the association of the RA/RE ratio with ESKD incidence in 212 Pima Indians with T2D who underwent measures of GFR (iothalamate) and RPF (p-aminohippurate). RA/RE ratio’s association with kidney structural lesions was also examined in a subset of 111 participants. Of the 212 subjects (29% men; mean age 52 years, diabetes duration 22 years, MAP 92 mmHg, HbA1c 10.1%, GFR 111 ml/min; median ACR 99 mg/g), 57 progressed to ESKD during median follow-up of 18.4 years. Cox regression, adjusting for sex, baseline age, diabetes duration, HbA1c, renin-angiotensin system blocker use and GFR, indicated that each 1 SD increment in the RA/RE ratio conferred higher risk of ESKD (4.19; 95%CI 2.18-8.04). In addition, the correlation between the RA/RE ratio and mesangial fractional volume, a key predictor of DKD progression (R2=15%, P&lt;0.0001), was stronger than the correlation between GFR and mesangial fractional volume (R2=7%, P=0.004). Elevated RA/RE ratio, reflective of low P&lt;glo, strongly associates with incident ESKD, independent of GFR, and with the glomerular structural lesion that best predicts this ESKD progression. These data, directly challenging the hypothesis that intraglomerular hypertension drives DKD, are derived from whole-kidney GFR and RPF, and therefore do not necessarily reflect single-nephron function. Nevertheless, identifying the mechanisms underlying this hemodynamic imbalance and its potential ischemic influences may provide new therapeutic targets.

Disclosure
P. Saulnier: None. H.C. Looker: None. M. Mauer: None. R.G. Nelson: None. P. Bjornstad: Advisory Panel; Self; XORTX Therapeutics Inc. Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Novo Nordisk Foundation. Research Support; Self; Horizon Pharma.

Funding
American Diabetes Association (1-08-CR-42 to R.G.N.); National Institute of Diabetes and Digestive and Kidney Diseases
312-OR: Gender-Specific Effects on Hepatic Fat Metabolism in Type 2 Diabetes before and after Remission
Authors: AL-MRABEH AHMAD , MELHEM SHADEN , ZHYZHNEUSKAYA SVIATLANA V. , PETERS CARL , BARNES ALISON C. , HOLLINGSWORTH KIEREN G. , SATTAR NAVEED , LEAN MICHAEL E. , TAYLOR ROY 
Published: June 2020

Men are more susceptible to type 2 diabetes and NAFLD than women, possibly secondary to differences in hepatic lipoprotein metabolism. The Tyneside cohort of Diabetes Remission Clinical Trial (34M/30F, 52.3±8.0 years, BMI 35.1±4.5kg/m2) were studied at baseline and to 24 months after weight loss. 3-point Dixon MRI was used for intra-organ fat. Hepatic VLDL-TG production was measured using a competitive blocking method. In the nondiabetic group, both liver and pancreas fat differed markedly in men and women (5.4± 1.1 vs. 3.4±0.1%, p=0.005, and 7.6±0.5 vs. 4.7±0.4%, p=0.0006, respectively). In diabetes, both liver and pancreas fat were similar in men and women at baseline (15.4±1.9 vs. 16.9±1.9%, p=0.57; and 8.5±0.4 vs. 8.4±0.5%, p=0.66, respectively). They decreased similarly after weight loss in both men and women (liver fat: 2.6±0.6% and 3.6±0.7%; pancreas fat: 7.6 ±0.4% and 7.5±0.5%, p&lt;0.0001 vs. baseline for both). VLDL-TG production was also similar at baseline (554±39 vs. 559±33mg/kg/day, p=0.96) and after weight loss (418±28 vs. 448±37mg/kg/day, p=0.29). Women had a lower VLDL-TG pool size (p=0.002), lower plasma VLDL-TG (p&lt;0.0001), lower fasting glucagon (p&lt;0.05), higher adiponectin (p&lt;0.001), and lower visceral adipose tissue (p&lt;0.0001) volumes than men regardless of diabetes status. However, diabetic women had higher: subcutaneous fat (p&lt;0.0001), leptin (p&lt;0.0001), fasting NEFA (p=0.004), GDF-15 (p=0.044), and FGF-21 (p=0.008). After 24 months of intervention, men and women remained significantly different in VLDL-TG pool, NEFA, SAT, VAT, leptin, and adiponectin (p&lt;0.05 for all). Women are likely to process lipoproteins more rapidly and safely store VLDL-TG. This minimizes delivery of toxic lipid metabolites from VLDL-TG to pancreatic islets. These data demonstrate important gender differences in hepatic fat handling, and underscore the importance of considering this when designing metabolic studies.

Disclosure
A. Al-Mrabeh: None. S. Melhem: None. S.V. Zhyzhneuskaya: None. C. Peters: Speaker’s Bureau; Self; Sanofi-Aventis. A.C. Barnes: None. K.G. Hollingsworth: None. N. Sattar: Advisory Panel; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Pfizer Inc., Sanofi. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. M.E. Lean: None. R. Taylor: Speaker’s Bureau; Self; Novo Nordisk Foundation.

Funding
Diabetes UK
313-OR: Diurnal Pattern of Meal Tolerance in Type 2 Diabetes
Authors: YADAV YOGESH R. , ROMERES DAVIDE , RUCHI FNU , SAWLEH SAFIA , CARTER RICKEY , BASU ANANDA , BASU RITA 
Published: June 2020

The existence of a diurnal pattern of post prandial glucose tolerance is relevant for management of patients with type 2 diabetes (T2D). We studied 10 healthy (4M) and 9 T2D (6M) subjects matched for age (56±3 vs. 58±3 yrs) and BMI (29±2 vs. 32±2 kg/m2). OGTT was done in healthy subjects to rule out diabetes. Identical mixed meals (8 kcal/kg/meal; 75 gm carb) were ingested during breakfast (B), lunch (L), and dinner (D) at 0700, 1300, and 1900 h in randomized latin square order with one labeled test meal/day on 3 consecutive days. Physical activity was kept same. Postprandial glucose turnover was measured utilizing the triple tracer technique modified with all stable isotopes ([1-13C] Glucose, [2-13C] Glucose and [6, 6-2H2] Glucose). Results shown in Fig 1. Fasting and post-meal glucose were higher while fasting and post-meal insulin and C-peptide concentrations lower in T2D for all three meals compared to healthy. Although meal glucose appearance did not differ between meals in either group, fasting endogenous glucose production (EGP) was higher, percent suppression of EGP lower in T2D and glucose disappearance (corrected for urine glucose loss) lower in T2D than healthy for all meals consumed. This data correlates with lower insulin sensitivity, B-cell responsivity to glucose and disposition index in T2D than healthy throughout the day. Our results suggest an emerging diurnal pattern to glucose tolerance and fluxes in humans, and that the pattern is different in T2D.

Disclosure
Y.R. Yadav: None. D. Romeres: None. F. Ruchi: None. S. Sawleh: None. R. Carter: None. A. Basu: Consultant; Spouse/Partner; GENFIT. Research Support; Spouse/Partner; AstraZeneca. R. Basu: Consultant; Self; GENFIT. Research Support; Self; AstraZeneca.

Funding
National Institutes of Health (R01DK029953 to R.B.), (R01DK085516 to A.B.), (DK059637, DK020593)
321-OR: Deletion of 14-3-3ζ in Pancreatic ß-Cells Increase Mitochondrial Activity and Insulin Secretion
Authors: MUGABO YVES , GALIPEAU MARIA , TAN JU JING , FADZEYEVA EVGENIA , GRYGORCZYK RYSZARD , LIM GARETH E. 
Published: June 2020

Pancreatic β-cells continuously sense blood glucose levels and secrete insulin to maintain normoglycemia. In β-cells, ATP generated by glycolysis promotes the closure of ATP-sensitive K+ channels, thereby increasing intracellular calcium and ultimately insulin secretion. 14-3-3 proteins, and in particular 14-3-3ζ, have been found to regulate ATP synthase and mitochondrial respiration, suggesting that members of this family of scaffold proteins in β-cells may influence glucose-stimulated insulin secretion (GSIS) and glucose homeostasis. To date, we have identified critical contributions of 14-3-3 proteins to GSIS. In mouse and human islets, pan-inhibition of 14-3-3 proteins with cell-permeable inhibitors potentiated ex-vivo GSIS. This was associated with increased mitochondrial function, as oxygen consumption and ATP synthesis rates were significantly enhanced. Moreover, increased ATP production was confirmed with luciferase-based assays. Of the seven isoforms, we previously reported critical metabolic roles of 14-3-3ζ in glucose homeostasis, and to understand its role in β-cells, β-cell-specific knockout mice (Ins1CreThor:14-3-3ζfl/fl, β-KO) were generated. When compared to control mice, no differences in body weights or glucose and insulin tolerance were observed, but β-KO mice displayed significantly enhanced insulin secretion following i.p. glucose (2 g/kg), and ex vivo islet perifusion studies revealed enhanced 2nd-phase secretion of GSIS from β-KO islets. Similar to pan-14-3-3 inhibition, increased mitochondrial activity and ATP synthesis were detected in islets of β-KO mice.
In summary, these results demonstrate critical functions of 14-3-3ζ and its related proteins in mitochondrial activity in β-cells and the regulation of GSIS. These data also suggest that 14-3-3ζ inhibition may represent a promising target to enhance pancreatic β-cell function in the context of diabetes.

Disclosure
Y. Mugabo: None. M. Galipeau: None. J. Tan: None. E. Fadzeyeva: None. R. Grygorczyk: None. G.E. Lim: None.

Funding
Canadian Institutes of Health Research; Canada Research Chairs Program (PJT-153144)
322-OR: Impairment of Alpha-Cell Bioenergetics Contributes to Increased Basal Yet Decreased Glucose Stimulated Oxygen Consumption Rates of Isolated Human Pancreatic Islets in T1DM and T2DM
Authors: DOLIBA NICOLAI M. , ROZO ANDREA V. , QIN WEI , ROMAN JEFFREY , LIU CHENGYANG , NAJI ALI , KAESTNER KLAUS H. , STOFFERS DORIS A. , MATSCHINSKY FRANZ 
Published: June 2020

Fuel stimulated hormone release (HR) and the oxygen consumption rates (OCR) of isolated normal pancreatic islets are positively correlated illustrating that cellular energy state is a critical determinant of stimulus-secretion coupling. We investigated the relationship between hormone release and OCR in islets from donors with T1DM and T2DM, using unique oxygen measurement technology and optimized perifusion protocols. HR and OCR were quantified in 20 human donor islet preparations obtained from the Human Islet Resource Center at the University of Pennsylvania within 3-4 days after isolation (5 each of nondiabetic, T1DM, T2DM and anti-islet AutoAntiBody positive (AAB+). A physiological amino acid mixture (4mM) was used to stimulate glucagon release, then 3 and 16.7mM glucose were added to stimulate insulin release and inhibit glucagon release. Respiration was then uncoupled with FCCP and finally blocked by NaN3. Basal OCR was increased in islets from AAB+, T1DM and T2DM donors compared to controls. Low glucose failed to increase OCR in T1DM and T2DM islets while high glucose-stimulated OCR was both decreased and delayed. Glucose stimulated insulin release much less effectively and failed to suppress glucagon release in both T1DM and T2DM islets. AAB+ islets showed normal insulin release but lacked glucose suppression of glucagon release. The observation of increased basal-OCR of islets in all diabetes related conditions and reduced glucose-stimulated-OCR in T1DM and T2DM islets unrelated to hormone release rates is striking and indicates a profound alteration of bioenergetics regulation in these conditions hitherto unrecognized. Common to this pathophysiology are an increase in relative alpha-cell mass (T1DM and T2DM) or a functional defect of these cells (AAB+) providing a plausible explanation for this phenomenology and implying impaired alpha-cell energy metabolism.

Disclosure
N.M. Doliba: None. A.V. Rozo: None. W. Qin: None. J. Roman: None. C. Liu: None. A. Naji: None. K.H. Kaestner: None. D.A. Stoffers: None. F. Matschinsky: None.

Funding
National Institutes of Health (UC4DK112217)
326-OR: Faricimab for Diabetic Macular Edema: A Novel Anti–Angiopoietin-2/Anti–Vascular Endothelial Growth Factor Bispecific Antibody in Clinical Trials
Authors: SHETH VEERAL , SAHNI JAYASHREE , STOILOV IVAYLO , WILLIS JEFFREY R. , WEIKERT ROBERT 
Published: June 2020

In the United States, diabetic retinopathy (DR) and diabetic macular edema (DME) are a leading cause of blindness among working-age adults. The introduction of vascular endothelial growth factor-A (VEGF) inhibitors has improved the management of DME and allowed regression of DR severity. However, DR/DME is a multifactorial disease, and targeting additional pathways holds promise for better outcomes. Angiopoietin-2 (Ang-2) is upregulated in the eyes of patients with diabetes and promotes vascular destabilization and inflammation. Faricimab, a novel bispecific antibody targeting both Ang-2 and VEGF, was evaluated in the BOULEVARD (NCT02699450) phase 2 trial for DME. Patients (N = 168 treatment-naïve [TN]; N = 61 previously anti-VEGF treated) were randomized 1:1:1 to intravitreal ranibizumab 0.3 mg, faricimab 1.5 mg (TN only), or faricimab 6.0 mg, every 4 weeks for 20 weeks followed by 16 weeks of observation. BOULEVARD met its primary outcome: faricimab 6.0 mg achieved greater mean gains (letters) from baseline in best-corrected visual acuity than ranibizumab at week 24 in TN patients (faricimab 6.0 mg, +13.9; faricimab 1.5 mg, +11.7; ranibizumab, +10.3; faricimab 6.0 mg vs. ranibizumab, +3.6; P = 0.03; 80% CI, 1.5, 5.6). The Early Treatment Diabetic Retinopathy Study DR Severity Scale (DRSS) was used to score vascular abnormalities and disease severity on color fundus images. A change of ≥ 2 steps is considered clinically significant. The proportion of TN patients with ≥ 2-step improvement from baseline at week 24 on the DRSS was 38.6%, 27.7%, and 12.2%, respectively. There were no new or unexpected safety outcomes with faricimab.
In conclusion, faricimab achieved better vision outcomes versus anti-VEGF monotherapy in TN patients, suggesting Ang-2 is a viable target for DR/DME. Phase 3 trials YOSEMITE (NCT03622580) and RHINE (NCT03622593) for faricimab in DME are ongoing.

Disclosure
V. Sheth: Consultant; Self; Genentech, Inc. J. Sahni: Employee; Self; Roche Pharma. Stock/Shareholder; Self; Roche Pharma. I. Stoilov: Employee; Self; Genentech, Inc. J.R. Willis: Employee; Self; Genentech, Inc. R. Weikert: Employee; Self; Roche Pharma.

Funding
F. Hoffmann-La Roche, Ltd.; Genentech, Inc.