bluuebunny/crossref_metadata_2025_split huggingface dataset:
497-P: Combination Epigenetic Therapy Normalizes Epithelial Wound Healing and Stem Cell Marker Expression in Human Organ-Cultured Diabetic Corneas
Authors: LJUBIMOV ALEXANDER V. 
Published: June 2024

Diabetes mellitus (DM) is a major cause of vision loss worldwide. Diabetic corneas have epithelial alterations such as impaired wound healing, possibly due to dysfunctional limbal epithelial stem cells (LESC). We previously used gene therapy and DNA demethylation to modulate DM-altered proteins cathepsin F (increased in DM), c-Met (decreased in DM), and Wnt-5a (decreased in DM) to stimulate wound healing and LESC marker expression. Here, we used combined therapy with a DNA methylation inhibitor and a nanobioconjugate (NBC) targeting cathepsin F and c-Met. Human donor diabetic organ-cultured corneas (6 pairs) were treated with 20 µM of biodegradable NBC based on polymalic acid scaffold containing antisense oligonucleotides (AON) to cathepsin F and miR-409 (c-Met inhibitor) or control scrambled AON twice for 2 days, with 20 µM of DNA demethylator zebularine or DMSO control for 2 days. One cornea received combined treatment, and the fellow one, combined controls. Healing of 5-mm epithelial wounds made with 1-heptanol was monitored, and marker expression was examined by immunostaining or western blot. Organ-cultured DM corneas treated with combined zebularine and NBC suppressed DNA methyltransferase 1 and cathepsin F, and increased Wnt-5a and c-Met. This resulted in significant decrease (by 38.4%, p&lt;0.02) of corneal epithelial wound healing time vs. DMSO and control NBC. Zebularine alone stimulated healing by 29.4%, and NBC alone, by 20.4%. Combination treatment increased the expression of putative LESC markers, keratins 15 and 17. DM markers integrin α3β1 and nidogen-1, and wound healing mediators p-Akt and p-p38 also had increased staining. There was no change in activated caspase-3 staining, indicating lack of treatment toxicity.Combination therapy with DNA methylation inhibitor and NBC targeting diabetes-altered protein markers may thus have a potential for the treatment of impaired diabetic corneal epithelial wound healing.

Disclosure
A.V. Ljubimov: None.

Funding
National Institutes of Health (EY013431; EY031377; EYEY025377)
499-P: Association between Diabetic Retinopathy and Number of Urinary Exfoliated Proximal Tubule Kidney Cells
Authors: HL WU HENRY , THE NGUYEN LONG , BHAGAVATH VENKATESHA , GOLDYS EWA , POLLOCK CAROL , SAAD SONIA 
Published: June 2024

Introduction & Objective: Emerging evidence suggests cell exfoliation could be operating under the control of cell metabolism. Recent studies indicate kidney cell exfoliation into urine may reflect metabolic status. Proximal tubule cell (PTC) exfoliation can be particularly sensitive to hyperglycemia in diabetes mellitus (DM) as glucose entry into PTCs is insulin independent. While it appears that number of urinary exfoliated PTCs increases with DM, it is unclear if there are associations between number of exfoliated PTCs with diabetic severity and co-morbidities. Our study aims to explore this.
Methods: Adults age ≥ 18 yrs with type 1 or 2 DM were included. Collected urine samples were stored at -80°C. On assessment, exfoliated PTCs were extracted from thawed urine using a validated specific immunomagnetic separation method based on anti CD13 and anti SGLT2 antibodies. Number of PTCs present was visualized using brightfield microscopy. A Poisson regression model adjusting for HbA1c%, eGFR (ml/min/1.73m2), presence of diabetic retinopathy (DR), cardiovascular events (CVE) history, age (yrs), sex, ethnicity, BMI, urine volume (ml) collected, estimated urinary creatinine clearance rate, serum creatinine, uACR and blood pressure (mmHg) as variables was constructed to determine association with mean exfoliated PTCs. Incidence rate ratios (IRR) determined significance of association.
Results: Eighty four patients with DM were included. Mean age is 63.8 yrs (std dev 11.6) and 81% are male. Each 1% increase in HbA1c% was associated with an increase of 1.03 times in mean exfoliated PTCs (IRR 1.03, 95%CI 1.01-1.04, p=0.007). Presence of DR was associated with an increase of 1.68 times in mean exfoliated PTCs (IRR 1.68, 95%CI 1.07-2.62, p=0.024). There were no significant associations between eGFR or CVE history with mean exfoliated PTCs.
Conclusion: Our results indicate increased shedding of PTCs into the urinary tract in patients with DM with poorer glycemic control and presence of DR.

Disclosure
H. Wu: None. L. Nguyen: None. V. Bhagavath: None. E. Goldys: None. C. Pollock: Advisory Panel; AstraZeneca, Vifor Pharma Management Ltd. Speaker's Bureau; Eli Lilly and Company, Boehringer-Ingelheim, Novartis AG, Janssen Scientific Affairs, LLC, Otsuka America Pharmaceutical, Inc., AstraZeneca, Vifor Pharma Management Ltd., Merck Sharp & Dohme Corp. S. Saad: None.
501-P: Neutrophil Extracellular Traps Contribute to Retinal Fibrosis Development in Diabetic Retinopathy
Authors: MONICKARAJ FINNY , DAS ARUP , SMOAKE JANE 
Published: June 2024

Purpose: Retinal fibrosis, characterized by fibroblasts, myofibroblasts, and extracellular matrix formation, occurs on the surface of the retinas following retinal neovascularization and vitreous hemorrhage. We have previously shown the contribution of neutrophils in the blood-retinal barrier alteration in an animal model of diabetic retinopathy (DR). We evaluated the hypothesis that the neutrophil signaling pathway contributes to the development of retinal fibrosis in DR.
Methods: Neutrophil extracellular traps (NETs) were prepared by treating human neutrophils with 25 mM glucose and 250ug advanced glycation endproducts. Transendothelial resistance of NETs and disulfiram (NET inhibitor) in human retinal endothelial cells was measured by electric cell-substrate Impedance Sensing (ECIS). The mRNA and protein expression of NETs, fibrosis, and endothelial mesenchymal transition (EndoMT) markers were analyzed on Streptozotocin-induced diabetic mice (3 months). NETs marker (Citrullinated Histone H3) was measured on serum samples of diabetic and nondiabetic subjects (n=10 in each group).
Results: Endothelial monolayer permeability was increased by NETs and significantly reduced by 10μM disulfiram. mRNA expression of EndoMT markers (TGFb1, MMP2, MMP9, ICAM1, VCAM1, & VE-Cad) and protein expression of NETs markers (PAD4 & Cit H3) were significantly increased in the retinas of diabetic animals compared with nondiabetic. Serum levels of Cit H3 were significantly increased in diabetic compared with nondiabetic subjects.
Conclusions: Overall, we have shown evidence that neutrophil extracellular traps triggered by neutrophil infiltration in diabetes play an essential role in EndoMT process and fibrosis. Targeting the NETs may be a potential therapeutic approach to preventing retinal fibrosis formation and traction retinal detachment.

Disclosure
F. Monickaraj: None. A. Das: None. J. Smoake: None.

Funding
NIH 5R01EY0286061I01BX005348-01A1
505-P: The Prevalence, Risk Factors and Predictors of Diabetic Retinopathy in Patients with Type 1 and Type 2 Diabetes in Riyadh, Saudi Arabia
Authors: ALMAZROU LULWA R. , SHBEAR ABDULRHMAN A. , ALZAHRANI SAAD H. , BREMA IMAD 
Published: June 2024

Introduction & Objectives: Diabetic retinopathy(DR) is associated with significant visual impairment and quality of life in people living with diabetes, however, studies on the prevalence and risk factors from Saudi Arabia have been inconsistent, hence the aim of this was to define the prevalence, risk factors and predictors of DR in a large sample of subjects with type 1 diabetes (T1DM) and T2DM.
Methods: This was a cross-sectional study that included subjects with both T2DM and T1DM (if duration &gt; 5 years) who attended the diabetes clinics at King Fahad Medical City in Riyadh between January 2022 and December 2022. Data are presented as Mean ± SD.
Results: The study sample included 1399 subjects of whom 566(40.5%) had T1DM and 833 (59.5 %) subjects had T2DM. Mean Hba1c for T1DM subjects was 8.8 ± 3.0 %, mean diabetes duration 10.2 ±5.6 years, and mean Time in Range (TIR) was 42.7 ± 18 % (N=354 subjects). Mean HbA1c for T2DM subjects was 7.8 ± 1.5 %, mean diabetes duration was 14.1 ± 8.8 years and mean TIR was 52.7 ± 25 (N=139). The prevalence of DR in the overall study population was 20.0 % (280/1399) with the majority ( 86.5 %) in the Mild and Moderate Non-Proliferative DR stages. The prevalence of DR in T1DM & T2DM subjects was 12.7 % and 24.8 %, respectively. Subjects with T1DM & DR were significantly older and had longer diabetes duration while subjects with T2DM & DR were older, had longer diabetes duration, higher Systolic BP, higher urinary albumin/Creatinine ratio( UACR) and lower estimated GFR. Logistic regression showed that in T1DM subjects, longer diabetes duration, lower TIR and higher glucose variability were independently associated while, longer diabetes duration and higher UACR were independently associated with DR in T2DM subjects.
Conclusion: In a large sample of Saudi subjects with diabetes, the prevalence of DR was 20 %. Efficient screening and targeting modifiable risk factors are important measures in the prevention as well as avoidance of progression of DR.

Disclosure
L.R. AlMazrou: None. A.A. Shbear: None. S.H. Alzahrani: None. I. Brema: None.

Funding
KFMC Research Centre
506-P: Branched-Chain Amino Acids Promote Occurrence and Development of Cardiovascular Disease Dependent on Triglyceride Metabolism via Activation of the mTOR/SREBP-1/Betatrophin Pathway
Authors: ZHANG JIE , HU WEN 
Published: June 2024

Background: Branched-chain amino acids (BCAAs) has been associated with the development of cardiovascular disease (CVD). However, the underlying mechanism remains uncertain.
Methods: The clinical study included 1302 subjects guided by diet and exercise intervention for 4 years and subsequent follow-up. We established a hyperbranched-chain aminoacidemia rat model induced by high fructose diet (HFTD). Additionally, we investigated the relationship between BCAAs and TG level and its regulatory mechanism in vitro.
Results: As baseline BCAA percentile increased, subjects were more likely to have a higher prevalence and incidence of diabetes, non-alcoholic fatty liver disease, and CVD risk. Both individual BCAAs and total BCAAs were independently associated with subsequent CVD risk. HFTD led to insulin resistance (IR) and higher levels of BCAAs in the rat model. Further investigation indicated that HFTD led to IR via the IRS-1/Akt/GSK-3β pathway and betatrophin expression was increased. Metformin significantly reversed the above effects. In vitro, we found BCAAs increased TG levels by regulating the mTOR/SREBP-1/betatrophin signaling pathway.
Conclusions: BCAAs promote occurrence and development of cardiovascular disease dependent on TG metabolism via activation of the mTOR/SREBP-1/betatrophin pathway.

Disclosure
J. Zhang: None. W. Hu: None.

Funding
the National Natural Sciences Foundation of China (81700776)
513-P: Sustained Reduction of Atherogenic Lipoproteins Two Years after Modest Weight Loss in the POUNDS Lost Trial
Authors: THOMAS MELBIN , FURTADO JEREMY , SACKS FRANK , TONG JENNY 
Published: June 2024

Apolipoprotein C-III (ApoC3) delays clearance of VLDL and LDL. Lipoprotein subspecies that contain ApoC3 are most predictive of CHD in type 2 diabetes. Our study's objective was to determine if diet-induced weight loss would reduce the concentration of atherogenic lipoproteins including ApoC3.
Methods: The POUNDS LOST trial was a two-year interventional study where 811 participants were randomized into four diet groups with varying macronutrient compositions. Standard lipid panels were performed at 0, 6, and 24 months. Lipoprotein subspecies by ApoC3 content and density (VLDL, LDL & HDL) were analyzed for ApoC3, ApoB, ApoE, triglyceride and cholesterol concentrations at baseline and 24 months on ~100 samples in each diet group (age 53 ± 9 y, BMI 32 ± 4 kg/m2, 60% female). Samples. Data were analyzed utilizing STATA software to perform non-parametric tests and multivariate regression models on lipoprotein subspecies.
Results: On average, participants lost 7% of the baseline weight at 6 months and 5% at 24 months. There were significant reductions in total cholesterol (-10.4±26 mg/dL, p&lt;0.001), LDL-C (-5.7± 23 mg/dL, p=0.004), non-HDL-C (-11.4 ± 24 mg/dL, p&lt;0.001), and triglyceride (TG) (-31.6 ± 59 mg/dL, p&lt;0.001) as well as an increase in HDL-C (1.2± 7 mg/dL, p=0.02) at 6 months. The reduction in non-HDL-C and TG remained significant at 24 months, but changes in LDL-C, HDL-C or total cholesterol did not. At 24 months, despite an average 1.6% weight regain, plasma concentration of ApoC3 in LDL (p=0.02), HDL (p=0.03), and VLDL (p &lt; 0.001) remained lower than baseline. Weight change (0-24 months) was positively associated with changes in ApoC3 level independent of age, sex, race, BMI, and dietary assignment (r=0.03, p=0.002).
Conclusion: Even modest weight loss reduces the concentration of atherogenic lipoproteins and increases the protective lipoprotein concentrations in individuals who were overweight or obese. These effects appear sustainable despite weight regain.

Disclosure
M. Thomas: None. J. Furtado: Employee; Biogen. Stock/Shareholder; Biogen. F. Sacks: None. J. Tong: None.
515-P: Do Circulating Sphingolipid Species Correlate with Age? A Study in a Normoglycemic Population
Authors: ALIYE FETO NASER , ASUZU PEACE , STENTZ FRANKIE B. , WAN JIM Y. , DAGOGO-JACK SAMUEL , MANDAL NAWAJES 
Published: June 2024

Objective: Sphingolipids (SPL) in circulation have been associated with pathological outcomes of metabolic and cardiovascular diseases that are known to be influenced by aging. We sought to determine the age association of plasma SPL species in people with no diabetes.
Methods: We determined plasma levels (pmole/mL) of 58 SPL species, including ceramides (Cer), monohexosylceramides (MHC), sphingomyelins (SM), sphingosine (So), and sphingosine 1-phosphate (S1P) in 239 normoglycemic participants using LC-MS/MS after dividing them into five age groups, 19-29y (n=46), 30-39y (n=47), 40-49y (n=64), 50-59y (n=67), and ≥60y (n=15). Correlation analysis identified SPL species that differ significantly among the age groups and that significantly correlate with aging.
Results: We identified the ratio of C18:0/C18:1 in Cer, MHC, and SM differed significantly in different age groups along with some very-long-chain (VLC) species of MHC and SM, SM C14:0, total SM, and SM% of SPL, which remained significant after adjusting for gender, race, BMI, waist circumference, FPG, and 2hPG. Interestingly, Cer C18:1 (r=0.20, p&lt;0.01) positively correlated with aging, and the ratio of Cer C18:0/C18:1 (r= -0.27, p&lt;0.0001) and MHC (r= -0.23, p&lt;0.001) correlated negatively. While levels of So (r= -0.29, p&lt;0.0001) and MHC C26:0 (r= -0.20, p&lt;0.01), MHC C28:0 (r= -0.25, p&lt;0.0001), MHC C34:0 (r= -0.23, p&lt;0.001) and MHC ratio of C26:0/C26:1 (r= -0.27, p&lt;0.0001) and MHC% of SPL (r= -0.20, p&lt;0.01) correlated negatively, SM% of SPL (r=0.21, p&lt;0.001) correlated positively.
Conclusions: Our results show that the plasma concentration of certain SPL species and ratios differ with age and correlate differentially with age. Thus, alterations in SPL metabolism may be linked to aging and age-related disorders.

Disclosure
N. Feto: None. P. Asuzu: None. F.B. Stentz: None. J.Y. Wan: None. S. Dagogo-Jack: Consultant; Merck Sharp & Dohme Corp., Medtronic, Bayer Inc. Stock/Shareholder; Aerami. N. Mandal: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK128129, R01 DK067269, and DK 48411)
518-P: Advanced Glycation End Products Impair HDL Particles' Function of Cholesterol Efflux Capacity in Newly Diagnosed Type 1 Diabetes (InLipoDiab1 Study)
Authors: URUSKA ALEKSANDRA , GRZELKA-WOZNIAK AGATA , ROHATGI ANAND , FLOTYNSKA JUSTYNA , ZOZULINSKA-ZIOLKIEWICZ DOROTA 
Published: June 2024

Introduction: Type 1 diabetes (T1DM) is characterized by high serum HDL, which does not translate into a better cardiovascular (CVD) prognosis. It is probably related to the impaired function of HDL particles. One of the main functions of HDL is the anti-atherosclerotic role related to reverse cholesterol transport from macrophages in arterial walls (cholesterol efflux capacity-CEC). CEC is a proven CVD risk factor. The dysfunction of HDL particles may be the result of glycation. Metabolic memory phenomena revealed that glycation status at the onset of T1DM may be crucial for future prognosis. Objective: To evaluate the influence of advanced glycation end products (AGE) at the onset of T1DM on HDL CEC in adults with newly diagnosed T1DM.
Methods: The analysis comprised 164 patients (110 men, 67%) with newly diagnosed T1DM confirmed by the presence of autoantibodies, recruited to the Insulin Therapy and Lipoproteins' Profile in Type 1 Diabetes (InLipoDiab1) study. CEC was assessed by measuring the efflux of radiolabelled cholesterol from murine J774 macrophages to apolipoprotein B-depleted serum. AGE in the skin was measured by autofluorescence using an AGE Reader. The endpoint was the assessment of CEC at one year after diagnosis.
Results: After one year of observation, a significant negative correlation was demonstrated between AGE at onset and CEC at one year (Rs=-0.33, p&lt;0.001). Moreover, the multiple linear regression revealed an independent relationship between AGE at onset and HDL function at one year (beta=-0.25, p=0.02), adjusted for age, BMI, and smoking.
Conclusions: The higher glycation expressed as AGE at the onset, the worse CEC, a key anti-atherosclerotic HDL function in adults with T1DM, after a year of T1DM duration. These results support the need for early T1DM diagnosis, preferably before the glycation process develops, to improve the future CVD prognosis of people with T1DM.

Disclosure
A. Uruska: Other Relationship; Ascensia Diabetes Care, Novo Nordisk, Lilly Diabetes, Boehringer-Ingelheim, AstraZeneca. A. Grzelka-Wozniak: Consultant; Novo Nordisk. Other Relationship; Boehringer-Ingelheim, Novo Nordisk, AstraZeneca, Roche Diabetes Care, Sanofi. A. Rohatgi: Research Support; CSL Behring, Quest Diagnostics. Consultant; Johnson & Johnson Medical Devices Companies, Raydel. J. Flotynska: None. D. Zozulinska-Ziolkiewicz: Advisory Panel; Abbott, BIOTON. Speaker's Bureau; Boehringer-Ingelheim, Eli Lilly and Company, Ascensia Diabetes Care, Novo Nordisk, Medtronic, Sanofi, Servier Laboratories. Advisory Panel; Eli Lilly and Company.

Funding
Kosciuszko Foundation, National Agency Academic Exchange (NAWA)
520-P: Plasma Sphingolipid Profiles Correlate with Circulating Lipoproteins and Adiposity
Authors: MANDAL NAWAJES , GRAMBERGS RICHARD , ALIYE FETO NASER , WAN JIM Y. , STENTZ FRANKIE B. , DAGOGO-JACK SAMUEL 
Published: June 2024

Objective: Dysregulation of cholesterol and sphingolipids (SPL) is associated with metabolic diseases. This study tested the correlation between plasma sphingolipids and plasma cholesterols (Chl), triglycerides (TG), and adiposity factors in normoglycemic individuals.
Methods: We assayed plasma levels of 58 species of SPL, including ceramides (Cer), monohexosylceramides (MHC), sphingomyelins (SM), from 240 normoglycemic Black and White participants. SPL profiles were analyzed by LC-MS/MS and correlated with plasma profiles of high-density Chl (HDL), low-density Chl (LDL), TG, and total Chl, along with participants’ biometric indicators of adiposity (BMI, waist circumference, total fat mass, total lean mass, and trunk fat mass).
Results: The subjects’ mean age was 43.08 ± 12.02 y from 150 females and 90 males, 129 Black and 111 White, with BMI 29.44 ± 6.23 kg/m2, fasting glucose 91.35 ± 6.91 mg/dl and 2-hr plasma glucose 122.77 ± 26.32. We found the total plasma Cer, MHC, and SM correlated positively with total Chl (r=0.3, p&lt;0.001; r=0.23, p&lt;0.01; and r=0.22, p&lt;0.01) and LDL (r=0.3, p&lt;0.01; r=0.22, p&lt;0.01; and r=0.21, p&lt;0.05). Strong positive correlations were observed with MHC C26:1 and total Chl (r=0.34, p&lt;0.0001) and LDL (r=0.36, p&lt;0.0001), and total and very-long-chain (VLC) SM species with HDL (r=0.2, p&lt;0.05 and r=0.38, p&lt;0.0001). Strong negative correlations were observed with MHC C32:0 and SM C26:0/C26:1 ratio with HDL (r= -0.3, p&lt;0.001 and r= - 0.36, p&lt;0.0001), and in SM C16:0/C18:0 ratio with LDL (r= -0.3, p&lt;0.001). VLC-SM species and SM C16:0/C18:0 ratio correlated negatively with BMI (r=-0.2, p&lt;0.01; r= -0.25, p&lt;0.000), waist circumference (r= -0.2, p&lt;0.01; r= -0.2, P&lt;0,01), and trunk fat mass (r= -0.2, p&lt;0.05; r= -0.2, p&lt;0.05).
Conclusions: This study demonstrates novel associations between adiposity and circulating levels of certain SPL and lipoproteins. Thus, plasma SPL may provide additional insights, beyond routine lipid profile, on metabolic pathophysiology.

Disclosure
N. Mandal: None. R. Grambergs: None. N. Feto: None. J.Y. Wan: None. F.B. Stentz: None. S. Dagogo-Jack: Consultant; Merck Sharp & Dohme Corp., Medtronic, Bayer Inc. Stock/Shareholder; Aerami.

Funding
National Institute of Health (R01 DK128129)
53-PUB: Impact of Diabetes on Perinatal Outcomes in Mexico—A MIDO Early Childhood Analysis
Authors: ALBERTO MARTINEZ-JUAREZ LUIS , GALLARDO-RINCÓN HECTOR , MARTÍNEZ-SILVA GISELA , MONTOYA ALEJANDRA , ÁLVAREZ-HERNÁNDEZ DIEGO-ABELARDO , CAMACHO-MORE DIANA G. , ALBERTO DIAZ-MARTÍNEZ DANIEL , JAVIER MAGOS-VAZQUEZ FRANCISCO , OSWALDO VARGAS EDWIN , MORENO GUADALUPE E. , AGUILAR JUAN P. , SOFÍA DOMIT ANA , TAPIA-CONYER ROBERTO 
Published: June 2024

Understanding the impact of gestational and pregestational diabetes on perinatal outcomes is imperative given the high prevalence of type 2 diabetes and obesity in Mexico. This study delves into the effects on pregnancies and neonates in this demographic using MIDO® Early Childhood data, focusing on children under five.
We analyzed data from 5,436 children, comparing perinatal and neonatal parameters across three groups: pregnancies with no diabetes (PND), pregnancies with gestational diabetes (PGDM), and pregnancies with pregestational diabetes (PPD). The Kruskal-Wallis test was used for statistical significance. To assess associations, a multinomial logistic regression model was utilized.
Vaginal eutocic deliveries were most common in PND (53.4%), but cesarean sections were more frequent in PPD (76.2%) and PGDM (54.5%). Preeclampsia was more observed in PGDM (13.7%) and PPD (15.9%), versus PND (5.8%). The occurrence of polyhydramnios was also higher in PGDM (2.8%) and PPD (1.6%) compared to PND (0.6%). Neonates weighing below 1500 kg were significantly higher in PPD (4.8%) than in PND (1.1%) and PGDM (0.4%). NICU admissions at birth were elevated in PGDM (22.2%) and PPD (6.7%) relative to PND (5.2%). Analyzing the odds ratio for preeclampsia, we found an OR of 2.59 in PGDM and 3.06 in PPD, compared to PND. The OR for NICU admissions was 5.23 for neonates from PPD pregnancies (P&lt;0.0001).
These findings underscore substantial differences in perinatal and neonatal outcomes among the groups. Further research is vital to fully grasp the implications and costs, emphasizing the need for policy changes in prenatal and perinatal care.

Disclosure
L. Martinez-Juarez: None. H. Gallardo-Rincón: None. G. Martínez-Silva: None. A. Montoya: None. D. Álvarez-Hernández: None. D.G. Camacho-More: None. D. Diaz-Martínez: None. F. Magos-Vazquez: None. E. Vargas: None. G.E. Moreno: None. J.P. Aguilar: None. A. Domit: None. R. Tapia-Conyer: None.

Funding
Eli Lilly Global Health Partnerships