bluuebunny/crossref_metadata_2025_split huggingface dataset:
309-OR: IGF-1 Receptors, Not Insulin Receptors, on Mesangial Cells Are Accelerating Mesangial Expansion and Albuminuria in Streptozotocin-Induced Diabetic Mice
Authors: ISHIKADO ATSUSHI , SHINJO TAKANORI , YOKOMIZO HISASHI , MAEDA YASUTAKA , PARK KYOUNGMIN , QI WEIER , ST-LOUIS RONALD , LI QIAN , KING GEORGE L. 
Published: June 2020

Clinical studies have suggested that loss of insulin’s action and excessive IGF-1 levels in the glomeruli elevate the risk for diabetic kidney disease (DKD). To define the potential pathogenic role of IGF-1 and insulin signaling in DKD, we generated mice with selective loss of insulin receptor (IR) or IGF-1 receptor (IGF-1R) in the mesangial cells (MCs) by cross breeding IRflox/flox mice with Sm22α-Cre mice (SMIRKO) or IGF-1Rflox/flox mice with Myh11-Cre mice (SMIGF1RKO), and examined urinary albumin excretion (ACR) and mesangial expansion with 6 month duration of streptozotocin (STZ)-induced diabetes. IGF-1 levels were significantly increased by 1.5 fold in the renal cortex, but not in the plasma of all three types of diabetic mice. Diabetes induced elevation of ACR (2.0 fold), glomerular size and mesangial expansion (2.1 fold), in parallel with increased glomerular expressions of fibrosis-related (Tgfβ1, fibronectin and Col3a) and matrix (Has2) genes by 2-3 fold, significantly, in Wt and SMIRKO mice, but were prevented in diabetic SMIGF1RKO mice. In cultured MCs, IGF-1, at physiological levels, and insulin, only at supra-physiological levels, induced the expressions of Has2 (3.8 fold) and Tgfβ1 (1.7 fold). Deletion of IGF-1R, but not IR, in MCs inhibited both IGF-1 and insulin-induced expressions of Has2. Inhibitor of MAP kinase pathway, but not inhibitor of PI3 kinase reduced insulin or IGF-1-induced expressions of Has2 in MCs. IGF-1-induced phosphorylations of IGF-1R (39 fold), Akt (34 fold) and Erk/MAPK (8 fold) were significantly inhibited in both IR or IGF-1R-deleted MCs. Insulin-induced phosphorylations of IR-β (11 fold) and Akt (27 fold) were also decreased in IR-deleted MCs, but surprisingly increased in IGF-1R-deleted MCs. Thus, MAPK activation by elevated glomerular IGF-1 levels via IGF-1R, but not IR, on MCs, may contribute to the pathogenesis of DKD through induction of Has2 and fibrotic genes.

Disclosure
A. Ishikado: Employee; Self; Sunstar Group. Employee; Spouse/Partner; Sunstar Group. T. Shinjo: None. H. Yokomizo: None. Y. Maeda: None. K. Park: None. W. Qi: None. R. St-Louis: None. Q. Li: None. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc.
320-OR: Bariatric Surgery Improves Ca2+ Dynamics across Pancreatic Islets In Vivo
Authors: AKALESTOU ELINA , SUBA KINGA , NORIEGA LIVIA LOPEZ , CHABOSSEAU PAULINE L. , LECLERC ISABELLE , SALEM VICTORIA , RUTTER GUY A. 
Published: June 2020

Background: Bariatric surgery improves both insulin sensitivity and secretion in T2D. However, the impact on insulin secretion is difficult to monitor directly, requiring correction for insulin sensitivity. The degree to which surgery impacts β-cell function versus mass, and the time course over which these changes occur, also remain unclear.
Aim: To investigate the effect of bariatric surgery on β-cell function in vivo, we imaged Ca2+ dynamics prospectively at the cellular level in islets engrafted into the anterior eye chamber.
Methods: Ins1Cre mice were crossed to animals that express the genetic calcium indicator GCaMP6f behind a Lox PSTOP&lt;italic&gt;LoxP cassette. Isolated islets were engrafted into male C57BL6 mice maintained for 12 weeks on high fat/high sucrose diet (HFD). At pre- (-1) and post-operative weeks 4, 8 and 12, Vertical Sleeve Gastrectomy (VSG) (n=7) and sham (n=6) groups were anaesthetized, and islets imaged in the eye using a Nikon microscope equipped with a spinning disc, 488 nm laser and 20x/1.0 water immersion objective. Islets were scored as positive for wave activity when these were recurrent, had a defined origin and covered &gt;75 % of the image plane. Glucose (3g/kg) tolerance and insulin secretion were assessed in parallel.
Results: The VSG group demonstrated substantial weight loss during the first 4 weeks post-operatively but regained pre-operative weight by week 12. Nonetheless, VSG mice displayed significantly improved glucose tolerance and insulin secretion (p&lt;0.001) when compared to sham mice. VSG improved coordinated Ca2+ activity, with 100% of islets exhibiting enhanced wave readouts 8 weeks post surgery. Over the same time period islet wave activity dropped by 34% in the sham group, falling to zero discernible coordinated islet Ca2+ activity by week 12.
Conclusions: By imaging islet function in the eye in vivo we demonstrate that bariatric surgery leads to a time-dependent increase in glucose-induced Ca2+ dynamics of individual islets, likely to underlie increased insulin secretion.

Disclosure
E. Akalestou: None. K. Suba: None. L. Lopez Noriega: None. P.L. Chabosseau: None. I. Leclerc: Consultant; Spouse/Partner; Sun Pharmaceutical Industries Ltd. Research Support; Spouse/Partner; Servier. V. Salem: None. G.A. Rutter: Consultant; Self; Sun Pharmaceutical Industries Ltd. Research Support; Self; Servier, Sun Pharmaceutical Industries Ltd.

Funding
UK Wellcome Trust (212625/Z/18/Z); Rosetrees Trust (M825); UK Medical Research Council (MR/R022259/1); Harry Keen Diabetes UK Fellowship (BDA 15/0005317); European Union
333-OR: DMHCA Reduces the Development of Diabetic Retinopathy (DR) in db/db Mice by Lowering Cholesterol Levels and Altering the Transcriptomic Profile of Hematopoietic Stem Cells
Authors: VIEIRA CRISTIANO P. , FORTMANN SETH D. , LONGHINI ANA LEDA , LYDIC TODD A. , BUSIK JULIA V. , GRANT MARIA B. 
Published: June 2020

Diabetic dyslipidemia, common in type 1 and type 2 diabetes (T2D), contributes to the pathogenesis of DR. LXR activation enhances cholesterol removal by reverse cholesterol transport (RCT) and reduces inflammatory gene expression. Systemic inflammation in diabetes is mediated, in part, by myeloidosis in the bone marrow (BM), which contributes to the pathogenesis of DR. We sought to test whether the progression of DR could be reduced by administering the novel LXR modulator, DMHCA (8mg/kg/body weight/day), in a T2D mouse model for 6 months. Retinal tissue was assessed by flow cytometry and Mass spectroscopy. LXR activation by DMHCA reduced cholesterol levels through the conversion to oxysterols and demosterol and was associated with a reduction of inflammatory cells in the retina and systemic circulation. Increased levels of long-term (17±1 vs. 11±2 db/db) and decrease levels of multipotent progenitors (MPP) (35±1 vs. 41±2 db/db) were noted in total bone marrow cells from db/db mice. DMHCA reduced the production of granulocyte-progenitors (GMP) (16 ± 1 vs. 22±3 db/db) and restored levels of NRF-2 (1±0.2 vs. 3±1 db/db) in bone marrow (BM) of db/db. DMHCA increased the number of myeloid angiogenic cells in the systemic circulation of db/db (0.04%±0.003 vs. 0.01%±0.002 db/db). Single cell RNA-seq analysis was performed using hematopoietic stem cells (HSCs) from untreated db/db and DMHCA treated db/db bone marrow. DMHCA treated HSCs showed upregulated genes associated with the activator protein 1 (AP-1) complex. AP-1 complexes regulate different stages of HSC differentiation along most of the myeloid lineage. Together, these findings reveal that LXR activation, via DMHCA treatment, decreases systemic and tissue-specific inflammation by controlling the production of pro-inflammatory stem cells and reducing oxidative injury in the BM of T2D mice.

Disclosure
C.P. Vieira: None. S.D. Fortmann: None. A. Longhini: None. T.A. Lydic: None. J.V. Busik: None. M.B. Grant: None.

Funding
National Institutes of Health (EY025383, EY012601)
335-OR: A Successful Diabetes Management Model of Care in Long-Term Care Facilities
Authors: SY SARAH L. , MUNSHI MEDHA 
Published: June 2020

Objectives: The management of diabetes in long-term care (LTC) facilities requires facility staff to perform most diabetes self-care activities on the behalf of the residents. We describe a practical model of care to improve diabetes management in LTC facilities.
Design and Methods: A diabetes management model of care was developed and implemented at six LTC facilities over 4-year period. The components of the program included: 1) developing individualized curriculum, and educating interdisciplinary staff members, 2) educating patients and families, and 3) developing a practical clinical care algorithm. Staff members were trained to identify the most likely reasons for hypo- or hyperglycemic episodes and intervention strategies based on the causes.
Results: Over 500 LTC staff members were educated and achieved competence during the program implementation. The patients and families received on an average 12.5 education sessions per month in skilled nursing facilities, and 1.5 education sessions per month in nursing homes. A total of 1031 residents were screened to assess risk of hypo- or hyperglycemia on admission to LTC. During the first 2 weeks of stay, hypo- and hyperglycemic episodes occurred in 31.4% and 29.2% of residents respectively. Overall, 245 residents (23.8%) experienced ≥1 episode of hypoglycemia (glucose &lt;70mg/dl). Of those 245 residents, 66.5% had 1 event, 15.5% had 2 events, and 18.0% had ≥3 events. Similarly, 240 residents (23.3%) experienced ≥1 episode of hyperglycemia (≥3 consecutive glucose readings &gt;200 mg/dl) with 63.7% having 1 event, 17.9% with 2 events, and 18.4% having ≥3 events. The most common cause of either hypo- or hyperglycemia was found to be medication related. The hypoglycemia episodes resolved without recurrence in 73-90% cases and interventions reduced the number of events over time.
Conclusion: Implementation of a practical model of diabetes management in LTC facilities can improve staff education leading to improved diabetes management for all residents.

Disclosure
S.L. Sy: None. M. Munshi: Consultant; Self; Eli Lilly and Company, Sanofi.
344-OR: Slowed Metabolic Decline after Oral Insulin (OI) in Relatives at High Risk for Type 1 Diabetes (T1D)
Authors: SOSENKO JAY , PALMER JERRY P. , HALLER MICHAEL J. , SKYLER JAY S. , PUGLIESE ALBERTO , SCHATZ DESMOND 
Published: June 2020

We assessed whether OI slowed metabolic decline after 1 yr of treatment among highest risk relatives who participated in the Diabetes Prevention Trial-Type 1 (DPT1) and TrialNet (TN) T1D prevention trials for OI. As published, with a diagnosis of T1D as the endpoint, both OI trials (7.5 mg/day) were negative overall. However, subgroup analyses suggested efficacy for those at high risk in each trial (DPT1: higher titer of insulin autoantibodies; TN: lower first-phase insulin response). Thus, we assessed whether OI slowed metabolic decline among the OI trial participants at highest risk, defined by DPT1 Risk Scores over a 6.75 threshold (DPTRS; OGTT C-peptide and glucose, age, and BMI), above which T1D risk increases sharply as DPTRS increases. Of 73% in DPT1 and 89% in TN with 1 yr OGTTs, 32% in DPT1 (90/282; age: 8.7±4.8 yrs) and 35% in TN (118/340; age: 6.9±3.3 yrs) were in the highest risk groups (3 yr risks: 56% in DPT-1; 55% in TN). In the analysis, area under curve (AUC) C-peptide increased from baseline to 1 yr in both OI groups (DPT1: p&lt;0.01; TN: p&lt;0.05) but not in the placebo groups, while AUC glucose increased more in the placebo groups (DPT1: p&lt;0.01; TN: p&lt;0.01) than in the OI groups (DPT1: p&lt;0.05; TN: n.s.). Consistent with those changes, in both trials the 1 yr AUC C-peptide/AUC glucose ratio (x100; AUC ratio) was greater in the OI group than in the placebo group [DPT1: 2.86±1.06 vs. 2.42±1.03 (ng/ml)/(mg/dl); TN: 3.06±1.13 vs. 2.57±0.96 (ng/ml)/(mg/dl); p-value&lt;0.05 for each (baseline adjusted)]. For DPT1 and TN combined (no interaction for treatment between trials), the p-value for the AUC ratio difference was &lt;0.001. Of those with DPTRS &lt;6.75 (3 yr risk: 24% for both DPT1 and TN), the AUC ratio did not differ between OI and placebo.
In conclusion, when DPTRS was &gt;6.75 metabolic outcomes at 1 yr appeared similarly favorable for OI in the DPT1 and TN trials, suggesting OI slows insulin decline in those at high risk for T1D. Moreover, metabolic measures could be useful endpoints for T1D prevention trials.

Disclosure
J. Sosenko: None. J.P. Palmer: None. M.J. Haller: Advisory Panel; Self; SAB Biotherapeutics, Inc. J.S. Skyler: Advisory Panel; Self; Abvance Therapeutics, ADOCIA, Avotres, Boehringer Ingelheim Pharmaceuticals, Inc., Dance Biopharm Holdings, Inc., Immunomolecular Therapeutics, Intrexon, Oramed Pharmaceuticals, Orgenesis Inc., Sanofi, Tolerion, Inc., Viacyte, Inc. Board Member; Self; Applied Therapeutics, Dexcom, Inc., Intarcia Therapeutics. Consultant; Self; Novo Nordisk A/S. Research Support; Self; Tolerion, Inc. Stock/Shareholder; Self; Applied Therapeutics, Dexcom, Inc., Intarcia Therapeutics. A. Pugliese: None. D. Schatz: None.
347-OR: Trends in Glycemic Control among Youth with Diabetes: The Search for Diabetes in Youth Study
Authors: MALIK FAISAL , SAUDER KATHERINE A. , ISOM SCOTT , ROBERTS ALISSA J. , MAYER-DAVIS ELIZABETH J. , DOLAN LAWRENCE M. , DABELEA DANA , LAWRENCE JEAN M. , PIHOKER CATHERINE 
Published: June 2020

Objective: To describe temporal trends in glycemic control in youth-onset diabetes.
Methods: The study included 6399 SEARCH for Diabetes in Youth participants with diabetes &gt;1 year. Visit data was categorized into 3 time periods: 2002-2007, 2008-2013, and 2014-2019 and 3 groups of diabetes duration: 1-4, 5-9, and 10+ years. Participants contributed one randomly selected data point to each duration group. Stratified multivariable regression models were used to test differences in hemoglobin A1c (A1c) over time, adjusted for site, age, sex, race/ethnicity, health insurance status, and disease duration, both overall (with repeated measures) and for each duration group.
Results: Estimated mean A1c among individuals with type 1 diabetes (T1D) was different over the three periods with a higher mean A1c in 2014-2019 and 2008-2013 versus 2002-2007 (p&lt;0.01; Table). There was a temporal difference in mean A1c for T1D participants with diabetes for 5-9 years (p&lt;0.01) and for T2D participants with diabetes 10+ years (p&lt;0.01).
Conclusions: Despite increased availability of diabetes technology, newer therapies, and more aggressive glycemic targets over time, current youth and young adults with T1D in the U.S. have worse glycemic control than earlier cohorts. Similarly, participants with T2D diagnosed in childhood and diabetes duration of 10+ years exhibit the temporal trend of worse glycemic control in recent years.

Disclosure
F. Malik: None. K.A. Sauder: None. S. Isom: None. A.J. Roberts: None. E.J. Mayer-Davis: None. L.M. Dolan: None. D. Dabelea: None. J.M. Lawrence: None. C. Pihoker: None.

Funding
Centers for Disease Control and Prevention (1U18DP006131, U18DP006133, U18DP006134, U18DP006136, U18DP006138, U18DP006139, U18DP006136, U58/CCU019235-4, U01 DP000244, U18DP002710-01); National Institute of Diabetes and Digestive and Kidney Diseases (1UC4DK108173)
350-OR: A Novel Long-Acting GLP-1 Agonist (GL0034) Demonstrates Remarkable Efficacy on HbA1c, Weight Loss, and Triglycerides in a Model of Type 2 Diabetes, the db/db Mouse
Authors: THENNATI RAJAMANNAR , BURADE VINOD S. , VILSBØLL TINA , THORENS BERNARD , RUTTER GUY A. 
Published: June 2020

Glucagon-like peptide-1 receptor agonists (GLP-1RA) provide substantial reductions in HbA1c and significant body weight loss in patients with type 2 diabetes (T2D). GL0034 is a novel long-acting, human GLP-1RA. In cellular cAMP assays GL0034 has a half-maximal effective concentration of 80 pM on GLP-1R expressing cells, but no effect on cells expressing the GIPR or the glucagon receptor. Upon SC dosing in the db/db mouse every other day for 4 weeks, GL0034 doses of 1.5, 3, and 6 nmol/kg lowered HbA1c by 1.6%, 3.2%, and 3.4%, respectively; demonstrating greater activity than that achieved with a higher dose of semaglutide (2.8%) or dulaglutide (2.0%) (Table). At 6-nmol/kg dose, GL0034 also induced a significant decrease in body weight; furthermore, plasma triglycerides and glucagon were significantly reduced by ∼74% and ∼41%, respectively. These effects of GL0034 treatment were greater than those induced by semaglutide or dulaglutide. Together, our study demonstrates that GL0034 is a potent, selective, long-acting GLP-1RA, which displays improved control of glucose homeostasis, body weight, and dyslipidemia in diabetic mice as compared with GLP-1RAs currently used for the treatment of T2D. GL0034 may serve as a promising new GLP-1RA for T2D and obese patients with T2D.

Disclosure
R. Thennati: None. V.S. Burade: Employee; Self; Sun Pharmaceutical Industries Ltd. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp & Dohme Corp., Sanofi. B. Thorens: Other Relationship; Self; Servier. G.A. Rutter: Consultant; Self; Sun Pharmaceutical Industries Ltd. Research Support; Self; Servier, Sun Pharmaceutical Industries Ltd.
354-OR: Cotadutide (medi0382), a Dual Receptor Agonist with Glucagon-Like Peptide-1 and Glucagon Activity, Modulates Hepatic Glycogen and Fat Content
Authors: ROBERTSON DARREN , HANSEN LARS , AMBERY PHILIP , ESTERLINE RUSSELL L. , JERMUTUS LUTZ , CHANG YI-TING , PETRONE MARCELLA , JOHANSSON EDVIN , JOHANSSON LARS , SJÖBERG FOLKE B. , PARKER VICTORIA 
Published: June 2020

Background and Aims: Cotadutide, a dual receptor agonist with glucagon-like peptide-1 (GLP-1) and glucagon activity, is being researched for the potential treatment of nonalcoholic steatohepatitis. Given the known effects of glucagon on hepatic glycogen and lipid metabolism, the aim of this phase 2a study was to investigate the effect of cotadutide on hepatic glycogen.
Methods: In this double-blind, placebo-controlled study, 21 overweight or obese adults with type 2 diabetes mellitus (HbA1c ≤ 8%) were randomized to receive once-daily subcutaneous cotadutide (n = 12) or placebo (n = 9) for 28 days. Following 48 hours of standardized meals, serial magnetic resonance spectroscopy scans relying on signals from naturally abundant 13C were performed to measure glycogen, and liver fat was also estimated. Fasting amino acid and ketone levels were also assessed.
Results: Significant reductions from baseline in postprandial hepatic glycogen content were observed with cotadutide (-100.2 mmol/L; 90% CI: -150.2, -50.1) vs. placebo (+5.5 mmol/L; 90% CI: -47.2, 58.3; P = 0.023). Statistically significant reductions in hepatic glycogen content were observed across serial measures and after a 14-hour fast (P &lt; 0.05), with an overall change in glycogen AUC24h of -27.3% (P = 0.003) vs. placebo. In addition, a relative reduction in liver fat of 33.2% vs. placebo was reported (P = 0.006), and significant reductions in fasting alanine, glutamate, glycine, lysine, and threonine levels were also observed with cotadutide vs. placebo (all P ≤ 0.05). Beta-hydroxybutyrate and acetoacetate levels were not significantly different between the two arms.
Conclusions: Cotadutide promoted a generalized reduction in hepatic glycogen and selected amino acid levels. Substantial reductions in liver fat were also observed with cotadutide, suggesting glucagon receptor engagement.

Disclosure
D. Robertson: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. L. Hansen: Employee; Self; AstraZeneca. P. Ambery: Employee; Self; AstraZeneca. R.L. Esterline: Employee; Self; AstraZeneca. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. Y. Chang: None. M. Petrone: Employee; Self; AstraZeneca. E. Johansson: None. L. Johansson: Employee; Self; Antaros Medical AB. Stock/Shareholder; Self; Antaros Medical AB. F.B. Sjöberg: None. V. Parker: None.

Funding
AstraZeneca
36-LB: Linoleic Acid Derived Oxylipins, Memory, and Microvascular Retinal Complications in Patients with Type 2 Diabetes Mellitus
Authors: WONG SOPHIE K. , NGUYEN MICHELLE M. , MAJOR-ORFAO CHELSI , LANCTÔT KRISTA L. , HERRMANN NATHAN , OH PAUL , SHAH BAIJU R. , GILBERT JEREMY , ASSAL ANGELA , HALPERIN ILANA , YANG PEARL , PEDERSEN THERESA , TAHA AMEER , SWARDFAGER WALTER 
Published: June 2020

Introduction: Memory decline is accelerated in type 2 diabetes mellitus (T2DM), and it is thought that microvascular disease may be a contributor. Oxylipins, bioactive lipid species derived from polyunsaturated free fatty acids such as linoleic acid, can act on small vessels. Cytochrome p450 derived epoxides may be immunologically active, whereas their hydrolysis into diols by soluble epoxide hydrolase (sEH) may render them inactive or cytotoxic. We examine linoleic acid epoxide and diol concentrations in peripheral blood and their associations with memory performance and retinal microvascular disease in patients with T2DM or prediabetes.
Methods: Patients with T2DM or prediabetes were recruited from 3 sites. Memory was assessed via California Verbal Learning Test 2nd Edition (CVLT-II). Patient history of retinopathy was recorded. Serum oxylipin concentrations were measured via ultra-high-performance liquid chromatography tandem mass-spectrometry.
Results: In people with T2DM or prediabetes (n=76, 55% women, 63±9 years old, HbA1C=7.4±1.2% mmol/mol, duration of diabetes 8±10 years), 9.2% had retinopathy, and the mean CVLT-II was -0.07±1.01 Z-score units (indicating generally average performance). The linoleic acid derived epoxide 12(13)-epoxyoctadecenoic acid concentration was negatively correlated with CVLT-II performance (β=-0.298, p=0.003), whereas the diol derived from that species (12,13-dihydroxyoctadecenoic acid) was elevated in people with retinopathy (9.1±4.1 nM vs. 6.5±11.5 nM, U=72.0, p=0.008).
Discussion: Oxylipins generated by cytochrome p450 and sEH should be explored as potential biomarkers for cognitive complications and microvascular disease in T2DM. The observed relationships might suggest the presence of a cytochrome p450-mediated response that may generate differential response and lack benefit in T2DM, possibly due to sEH-mediated conversion of epoxides into diols, warranting further study.

Disclosure
S.K. Wong: None. M.M. Nguyen: None. C. Major-Orfao: None. K.L. Lanctôt: None. N. Herrmann: None. P. Oh: None. B.R. Shah: None. J. Gilbert: Speaker’s Bureau; Self; Abbott, Amgen, Ascensia Diabetes Care. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Dexcom, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi. A. Assal: None. I. Halperin: Advisory Panel; Self; Tandem Diabetes Care. Speaker’s Bureau; Self; Abbott, Boehringer Ingelheim (Canada) Ltd., Dexcom, Inc., Novo Nordisk Inc., Sanofi. P. Yang: None. T. Pedersen: None. A. Taha: None. W. Swardfager: None.

Funding
Canadian Institutes of Health Research (410010992)