bluuebunny/crossref_metadata_2025 huggingface dataset:
331-OR: Gestational Diabetes Knowledge Improves with Interactive Online Training Modules
Authors: KRUTILOVA PETRA , WILLIAMS ROXANN C. , MOREY REBECCA , FIELD CAROLE , BYRTH RONNI , TEPE MELISSA D. , HERRICK CYNTHIA J.
Published: May 2022

Background: GDM (gestational diabetes mellitus) increases the lifetime risk of maternal T2DM by 7-fold and increases the risk for maternal and fetal complications. Prenatal education on nutrition, exercise, and T2DM risk among women with GDM increases the likelihood of postpartum diabetes screening. However, access to diabetes education is limited. To address this gap, we created four GDM training modules for nurses and community health workers (CHW) and studied changes in knowledge, attitudes, and intentions before and after training completion.

Methods: Online modules (45-60 minutes each with interactive cases and integrated knowledge check questions) were distributed through multiple professional organizations to clinical staff providing care for women with GDM with optional pre- and post-evaluation surveys.Data were not normally distributed. We described baseline population characteristics, GDM knowledge, attitudes, and intentions using median score and interquartile range. We evaluated changes in scores on knowledge, attitude, and intention scales before and after training using non-parametric Wilcoxon matched pair signed rank tests.

Results: Seventy-eight individuals completed baseline evaluation (99% female, median age 40, 65% white non-Hispanic; 54% LPN/RN, 22% CHW, 24% other degree) . Nineteen individuals completed all 4 modules and post-training assessments. GDM knowledge improved significantly after training (median pretest - posttest score: 56% to 78%, p<0.001) . The biggest improvement in knowledge was noted in monitoring, medications, and hypoglycemia prevention (51% to 77%, p<0.001) . Intention to recommend diabetes prevention methods also increased after training (median pretest - posttest score: 35.5 to 39.4, max. score 40, p=0.009) .

Conclusion: Interactive online modules improved knowledge and intention to recommend diabetes prevention methods. Access to such curricula is critical for improving access to diabetes education among patients.

Disclosure

P.Krutilova: None. R.C.Williams: None. R.Morey: None. C.Field: None. R.Byrth: None. M.D.Tepe: Other Relationship; Merck & Co., Inc. C.J.Herrick: Consultant; Teladoc Health, Other Relationship; Eli Lilly and Company, Merck & Co., Inc.

Funding

NICHD K23HD096204NIDDK T32DK007120
332-OR: Success of Virtual Patient Simulation at Improving Comprehensive Management of Type 2 Diabetes
Authors: LARKIN AMY , LACOUTURE MICHAEL
Published: May 2022

We sought to determine if online, virtual patient simulation (VPS) -based continuing medical education (CME) can improve performance of diabetologists/endocrinologists (D/Es) and PCPs in comprehensive management of T2D.

Methods: The CME comprised a patient presenting at two different time points in a VPS platform that allows learners to order lab tests, make diagnoses, and prescribe treatments similar to actual practice. Tailored clinical guidance (CG) , based on current evidence, was provided, followed by opportunity to modify choices. Decisions were collected post-CG and compared with baseline (pre-CG) decisions using a McNemar’s test to determine P values. The activity posted July 8, 2021; initial data collected through December 7, 2021.

Results: 48 D/Es and 494 PCPs completed all decisions within at least 1 case and were included. Case 1: Primary Prevention: 48% relative increase of D/Es (56% pre-CG vs. 83% post-CG; P<.001) and 21% relative increase of PCPs (70% pre-CG vs. 85% post-CG; P<.001) who assessed glycemic control and CV risk. 425% relative increase of D/Es (8% pre-CG vs. 42% post-CG; P<.001) and 1150% relative increase of PCPs (4% pre-CG vs. 50% post-CG; P<.001) who accurately ordered treatments for primary prevention. Case 2: Secondary Prevention: 23% relative increase of D/Es (66% pre-CG vs. 81% post-CG; P<.05) and 11% relative increase of PCPs (76% pre-CG vs. 84% post-CG; P<.001) who assessed glycemic control and CV risk. 163% relative increase of D/Es (19% pre-CG vs. 50% post-CG; P<.01) and 103% relative increase of PCPs (29% pre-CG vs. 59% post-CG; P<.001) who accurately ordered treatments for secondary prevention. Continued Gaps: 58% of the D/Es and 50% of PCPs failed to provide effective primary prevention risk reduction in case one, and 50% of the D/Es and 41% of PCPs failed to provide effective secondary prevention risk reduction in case two.

Conclusion: This CME strategy improved evidence-based clinical decisions related to comprehensive management of T2D.

Disclosure

A.Larkin: None. M.Lacouture: None.

Funding

Eli Lilly and Company
341-OR: Enhanced Responsiveness of ß- and α-Cells to Glucagon-Like Peptide-1 (GLP-1) in Youth vs. Adults with Impaired Glucose Tolerance (IGT) or Drug-Naïve Type 2 Diabetes (T2D)
Authors: NADEAU KRISTEN J. , TJADEN ASHLEY H. , EHRMANN DAVID A. , ARSLANIAN SILVA A. , CAPRIO SONIA , EDELSTEIN SHARON , HANNON TAMARA S. , TEMPLE KARLA A. , XIANG ANNY , KAHN STEVEN E. ,   THE RISE CONSORTIUM
Published: May 2022

In the Restoring Insulin Secretion (RISE) Study, youth (Y) compared to adults (A) had enhanced β-cell (greater incremental C-peptide [CP] responses) and α-cell responsiveness (greater glucagon [GG] suppression) . As GLP-1 increases CP and decreases GG, we measured GLP-1 (Mercodia) during a 3-h oral glucose tolerance test (OGTT) in 65 Y (age: 14.2 y) and 65 A (51.0 y) to determine if greater GLP-1 release explained age-related differences in CP and GG responses. Groups were matched for sex (71% female) , race/ethnicity (29% white, 22% black, 37% Hispanic) and IGT/drug naïve T2D (80/20%) status and did not differ by BMI (36.7±6.0 vs. 35.3±4.1 kg/m2) . We calculated fasting, early (0-to-30 mins; ∆) and incremental area under the curve (iAUC) responses for G, CP and GLP-1, and decrements in GG (d∆; dAUC) . Y and A did not differ in fasting or OGTT glycemic responses, but Y had greater fasting CP, ∆CP and iAUC CP, more d∆GG suppression, and a trend for more diGG suppression, than A (Table) . Fasting GLP-1 was not different in Y vs. A, but stimulated GLP-1 was lower in Y throughout the OGTT.

In conclusion, in Y higher CP and lower GG during an OGTT, paired with lower GLP-1 concentrations, suggest that the enhanced β- and α-cell responsiveness to GLP-1 could be due to increased sensitivity of the islet cells to the incretin, rather than a primary increase in GLP-1 release.

Disclosure

K.J.Nadeau: None. S.E.Kahn: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc. T.Consortium: None. A.H.Tjaden: None. D.A.Ehrmann: None. S.A.Arslanian: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Other Relationship; AstraZeneca, Research Support; Eli Lilly and Company, Novo Nordisk. S.Caprio: None. S.Edelstein: None. T.S.Hannon: Advisory Panel; Eli Lilly and Company. K.A.Temple: None. A.Xiang: None.

Funding

American Diabetes Association (1-20-RISE-01) ; NIDDK, Department of Veterans Affairs, and Kaiser Permanente Southern California
346-OR: Race/Ethnicity-Specific Relationships of Physical Markers of Adiposity to Clamp-Measured Insulin Sensitivity (IS) and ß-Cell Function (ßCF) in Obese Youth
Authors: ROSENBERG JARED , CHO WONHEE , ARSLANIAN SILVA A. , KIM JOON YOUNG
Published: May 2022

Physical markers of adiposity including BMI, WC and WHtR have been utilized as physical surrogates of IS and βCF to examine type 2 diabetes risk but without attention to race/ethnicity specific differences. Herein, we examined race-specific differences in the relationships between those physical surrogates and clamp-measured IS and βCF in obese African American (AA) vs. American White (AW) youth. A total of 183 obese youth (age 14.6 ± 0.1 yrs [SE]) completed a hyperinsulinemic-euglycemic clamp to evaluate peripheral IS and a hyperglycemic clamp to measure 1st-phase insulin (1st-PhI) . In AW, BMI, WC and WHtR correlated significantly with peripheral IS and 1st-PhI while in AA with only peripheral IS (Table) . The relationships of BMI to peripheral IS and 1st-PhI were stronger in AW vs. AA youth, with no differences in the correlation coefficients by race for WC and WHtR (Table) . There was a larger decrease in peripheral IS from the lowest to the highest tertiles of BMIs in AW vs. AA youth (63 vs. 39%, interaction p<0.01) , with no interaction on 1st-PhI.The strong relationship of BMI with IS and 1st-PhI in AW but not AA youth may suggest that other factors besides BMI may play a role in the insulin resistance/hyperinsulinemia reported in AA youth. In AW youth, increases in BMI may be more detrimental for reductions in insulin sensitivity than is the case for AA youth.

Disclosure

J.Rosenberg: None. W.Cho: None. S.A.Arslanian: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Other Relationship; AstraZeneca, Research Support; Eli Lilly and Company, Novo Nordisk. J.Kim: n/a.

Funding

National Institute of Child Health and Human Development grant (K24-HD01357 and R01-HD27503) National Center for Advancing Translational Sciences Clinical and Translational Science Award (UL1TR000005) National Center for Research Resources grant (UL1RR024153)
35-OR: Multicenter MRI Assessment of the Pancreas in Type 1 Diabetes (MAP-T1D) Predicts Progression of Type 1 Diabetes
Authors: VIROSTKO JOHN , WRIGHT JORDAN J. , WILLIAMS JONATHAN M. , HILMES MELISSA A. , TRIOLO TAYLOR M. , BRONCUCIA HALI C. , DU LIPING , KANG HAKMOOK , RUSSELL WILLIAM E. , PHILIPSON LOUIS H. , KAY THOMAS , THOMAS HELEN E. , GREELEY SIRI ATMA W. , STECK ANDREA , POWERS ALVIN C. , MOORE DANIEL J.
Published: May 2022

Pancreas size, as measured by MRI, is smaller at the onset of T1D and in individuals at risk for T1D. To determine whether pancreas MRI predicts T1D progression, we measured pancreas size and shape longitudinally in Type 1 Diabetes TrialNet Pathway to Prevention study participants. To increase enrollment and expand this study across multiple TrialNet sites, we established the Multicenter Assessment of the Pancreas in T1D (MAP-T1D) group to develop harmonized MRI acquisition and image processing protocols and ensure the consistency of imaging results across sites. Using this standardized protocol (PMID: 34428220) , we performed longitudinal pancreas MRI in 41 multiple autoantibody-positive individuals (mean age y.o., range 8 - 45 y.o., 49% female) at three TrialNet Clinical Centers. Average time between study entry and diabetes diagnosis for individuals who progressed to Stage 3 was 54 months while non-progressors were followed for a median time of 63 months. Five study participants who developed Stage 3 T1D during follow up had a smaller pancreas (29.5 ± 9.0 ml vs. 54.8 ± 22.5 ml, p = 0.02) and smaller pancreas volume normalized by body weight (0.61 ± 0.18 ml/kg vs. 0.85 ± 0.23 ml, p = 0.03) at study entry compared with those who did not progress to Stage 3. We found that pancreas volume was stable over time, with no significant increase or decrease up to four years after the initial MRI (total of 123 MRIs) . There was no significant change in pancreas size in the five individuals who progressed to Stage 3 T1D. The shape of the pancreas at study onset was also different in the five individuals who progressed to Stage 3 T1D compared with non-progressors, with larger surface area to volume ratio (p = 0.02) , and shorter principal axes (p = 0.05, shortest axis; p = 0.02, second shortest axis) . These data suggest that small pancreas size and altered shape predicts progression from Stage 2 to Stage 3 T1D.

Disclosure

J.Virostko: None. L.H.Philipson: Advisory Panel; Nevro Corp., Research Support; Dompé, Novo Nordisk, provention BIo. T.Kay: None. H.E.Thomas: Research Support; Captix Biomedical, CSL Limited, Pandion Therapeutics, Procyon Technologies. S.W.Greeley: None. A.Steck: None. A.C.Powers: None. D.J.Moore: None. J.J.Wright: None. J.M.Williams: None. M.A.Hilmes: None. T.M.Triolo: None. H.C.Broncucia: None. L.Du: None. H.Kang: None. W.E.Russell: None.

Funding

NIDDK (R03DK129979, U24DK097771, UC4 DK106993, DK020593) ; JDRF International (3-SRA-2015-102-M-B, 3-SRA-2019-759-M-B) ; Thomas J. Beatson, Jr. Foundation (2021-003)
354-OR: Estimating the Relative Influence (RI) of Genetic Risk of Glycemic Traits on Osteoporosis and Fractures in 409,633 Participants in the UK Biobank Using Machine Learning
Authors: DESHMUKH HARSHAL , PAPAGEORGIOU MARIA , MARK-WAGSTAFF CHARLOTTE , AKBAR SHAHZAD , BHAIJI AMIRA , SHAH NAJEEB , SATHYAPALAN THOZHUKAT
Published: May 2022

Introduction: We used a machine-learning algorithm (gradient boosting) to test the association of genetic risk for glycemic traits with osteoporosis and fracture in the UK Biobank population.

Methods: The study was performed with 409,633 participants in the UKBIobank. We identified 4626 SNPs associated with glycemic traits from the NGHRI catalogue for GWAS studies. Weighted genetic risk scores (wGRS) were calculated using the effect estimates from the GWAS studies. We used a gradient-boosting machine-learning (GBM) model to identify the relative influence (RI) of baseline variables and wGRS of the glycemic traits on osteoporosis and self-reported all-cause fractures in the UK Biobank population. We split the data into training (2/3) and testing set (1/3) and calculated the discriminatory power of the models using the area under the curve (AUC) with the testing model.

Results: The study consisted of 409,633 individuals (53% females) with a median age of 58 (51-63) years and a median BMI of 26.7 (24.1-29.8) kg/m2. The study population had 41954 (10.2%) all-cause fractures and 4995 (1.2%) participants with osteoporosis. In the GBM model, top wGRS associated with all-cause fractures were wGRS for Type 1 diabetes (RI=4.49) and fasting glucose (4.17) . In contrast, the top wGRS associated with osteoporosis were wGRS for acute insulin response to glucose (RI=6.74) and Type 1 diabetes (RI=5.62) . Both models showed low to moderate discriminatory power with the area under the AUC of 0.57 (CI: 0.56-0.57) for fractures and 0.75 (CI: 0.74-0.76) for osteoporosis.

Conclusion: We showed a differential effect of wGRS for various glycemic traits on the risk of fractures and osteoporosis in the UK Biobank population. However, the machine-learning model with wGRS for glycemic traits demonstrated limited capacity to predict fractures and osteoporosis in the general population.

Disclosure

H.Deshmukh: None. M.Papageorgiou: None. C.Mark-wagstaff: None. S.Akbar: None. A.Bhaiji: None. N.Shah: None. T.Sathyapalan: n/a.

Funding

Dr Harshal Deshmukh is funded by NIHR clinical lectureship
361-OR: Proinsulin Processing Efficiency Differs in Youth and Adults with IGT or Untreated T2D
Authors: HANNON TAMARA S. , SAM SUSAN , TJADEN ASHLEY H. , EDELSTEIN SHARON , NADEAU KRISTEN J. , ARSLANIAN SILVA A. , CREE-GREEN MELANIE , EHRMANN DAVID A. , MATHER KIEREN J. , KAHN STEVEN E. ,   THE RISE CONSORTIUM
Published: May 2022

Disproportionately increased proinsulin (PI) relative to C-peptide (CP) is a marker of inefficient β cell PI processing. To determine whether PI processing differs between youth (Y) and adults (A) with impaired glucose tolerance (IGT) and drug naïve T2D, we measured PI and CP in 58 Y (81% IGT, 69% female, 26% white, 22% black, 40% Hispanic, BMI=37±6 kg/m2) and 322 A (71% IGT, 52% female, 47% white, 28% black, 19% Hispanic, BMI=35±5 kg/m2) in the Restoring Insulin Secretion (RISE) Study. We assessed fasting PI, CP, PI/CP, and acute PI (API) and CP (ACP) responses to glucose (Rg) (APIRg, ACPRg, APIRg/ACPRg) and arginine at maximal (Rmax) glycemic potentiation (APIRmax, ACPRmax, APIRmax/ACPRmax) during a hyperglycemic clamp. Fasting PI, CP, and PI/CP were higher in Y vs. A, suggesting PI processing in the fasted state is lower in Y (Table) . APIRg and APCPg were higher in Y, and APIRg/ACPRg was similar. APIRmax, but not ACPRmax, was lower in Y. Thus, APIRmax/ACPmax was lower in Y, suggesting PI processing at maximal β cell stimulation is greater in Y. These results suggest that increased fasting β-cell secretory demand in Y may decrease the time available for PI processing and cause the release of more immature granules during fasting. Y may utilize a larger pool of granules in which PI processing is more complete when secretory demand is maximal.

Disclosure

T.S.Hannon: Advisory Panel; Eli Lilly and Company. S.E.Kahn: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc. T.Consortium: None. S.Sam: None. A.H.Tjaden: None. S.Edelstein: None. K.J.Nadeau: None. S.A.Arslanian: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Other Relationship; AstraZeneca, Research Support; Eli Lilly and Company, Novo Nordisk. M.Cree-green: None. D.A.Ehrmann: None. K.J.Mather: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.

Funding

American Diabetes Association (1-20-RISE-01) ; NIDDK, Department of Veterans Affairs, and Kaiser Permanente Southern California
370-OR: Proinflammatory Stress Activates Neutral Sphingomyelinase 2 Based Generation of Ceramide-Enriched ß-Cell Exosomes
Authors: XU JERRY , SIMS EMILY K.
Published: May 2022

Data suggest that β cell exosomes, extracellular vesicles released by exocytosis of multivesicular endosomes (MVEs) , may act as paracrine effectors in islet health. However, mechanisms linking β cell stress to changes in exosomes and whether activation of these pathways can impact diabetes remain less explored. In other cells, the enzyme neutral spingomyelinase 2 (nSMase2) induces ceramide dependent MVE vesicle formation and release of ceramide-enriched exosomes. We hypothesized that β cell inflammatory stress engages ceramide-dependent exosomal formation pathways, and that ceramide-enriched exosomes could then impact surrounding β cells. To test this we treated INS-1 β cells with 24 hrs of 5 ng/mL of IL1β. nSMase 2 and ceramide expression were quantified with immunoblot and/or flow cytometry and exosomes were isolated using a tetraspanin bead-based pulldown. IL1β increased β cell nSMase2 expression and ceramide expression in concert. Direct nSMase2 activation with 24 hrs of 5-ng/mL Caffeic acid phenethyl ester (CAPE) also increased β cell ceramide staining. IL1β and CAPE treatments also yielded increased ceramide expression on β cell exosomes. Human islets exhibited similar increases in cellular nSMase2 and ceramide staining after 24-hr cytokine mix treatment (5ng/mL IL1β, 10ng/mL TNFα, and 100ng/mL IFNγ) . To test the potential for transfer of β cell exosomes to surrounding cells, we generated INS-1 cells with GFP tagged CD9 (exosome transmembrane protein) , which release GFP labeled exosomes. Flow cytometry staining in wild-type INS-1 cells after 24-hr transwell coculture with CD9-GFP cells showed that cocultured wild-type cells exhibited increased green fluorescence, suggesting transfer of CD9-GFP exosomes. Our findings suggest that nSMase2 activity may regulate β cell exosome subpopulations under conditions of inflammatory stress. Future work will interrogate impacts on exosome cargo and physiologic impacts of transfer on recipient cells.

Disclosure

J.Xu: None. E.K.Sims: Other Relationship; Medscape, Patent.

Funding

5 R01DK121929
380-P: Burden of Low Interstitial Fluid Glucose Levels among Type 2 Diabetes Patients with Chronic Kidney Disease and Its Associated Variables
Authors: TIAN KRISTY , ANG LI C. , GOH SU-YEN , BEE YONG MONG , CHOO JASON , TEH MING M.
Published: May 2022

Background: Type 2 diabetes (T2D) patients with chronic kidney disease (CKD) are at high risk of hypoglycemia due to decreased renal gluconeogenesis and clearance of diabetes medications. This study aims to quantify the burden of hypoglycemia in this population, and identify potential risk factors.

Methods: Outpatient T2D subjects with CKD (eGFR <60ml/min per 1.73m2) were recruited to wear a Freestyle Libre-Pro sensor for 2 weeks. Collected data was analyzed for low interstitial fluid glucose (IFG) burden. IFG values of less than 72mg/dL and 50mg/dL that persisted for at least 15 minutes were defined as ‘low sensor glucose (LSG) ’ and ‘very low sensor glucose (VLSG) ’ respectively. Occurrence of VLSG events were correlated with patient-reported symptoms. Univariate analysis with Poisson regression was performed to look for predictive factors for LSG and VLSG events.

Results: A total of 77 subjects with CKD were included in the study, 46 (59.7%) male and 31 (40.3%) female. The subjects were 67.9 ± 8.9 years old with duration of diabetes of 22.0 ± 12.1 years and HbA1c of 8.1 ± 1.9%. The subjects wore the sensor for 14.3 ± 1.6 days. Sixty-five subjects (84.4%) experienced a total of 612 LSG events (mean number of events per subject 8.0 ± 8.6) with total duration of 1834 ± 2812 minutes while 44 subjects (57.1%) experienced a total of 244 VLSG events (mean number of events per subject 5.6 ± 5.9) with total duration of 1080 ± 1838 minutes. Majority of subjects who experienced VLSG events (90.9%) did not report associated symptoms. Lower HbA1c and lower mean glucose were associated with LSG (rate ratio of 0.79 (0.70 - 0.89) and 0.71 (0.66 - 0.76) respectively with p values <0.05) . Similar results were found for VLSG events. Interestingly, the degree of renal impairment did not predict for LSG or VLSG events.

Conclusion: Clinicians must consider what appropriate glycemic targets should be for T2D patients with CKD as this modifiable risk factor is highly predictive of hypoglycemic events.

Disclosure

K.Tian: None. L.C.Ang: None. S.Goh: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Sanofi. Y.Bee: None. J.Choo: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, GlaxoSmithKline plc., Novartis AG, Consultant; AstraZeneca, Nitto Denko Asia Technical Centre, Novartis AG, Research Support; AstraZeneca, Nitto Denko Asia Technical Centre, Speaker's Bureau; Abbott, Bayer AG. M.M.Teh: None.
383-P: Clinical Practice Gap Analysis of Severe Hypoglycemia Assessment and Treatment in Patients with Diabetes
Authors: LARKIN AMY , LE ANNE , SCHRAND JULIE
Published: May 2022

Introduction: Understanding clinical practice gaps in the assessment and treatment of severe hypoglycemia in patients with diabetes can inform development of tools to improve physician practices. Methods: A survey instrument of 25 multiple choice, knowledge- and case-based questions allowed participants to assess their knowledge, attitudes, and confidence with regard to severe hypoglycemia. The survey was available online to physicians across the globe without monetary compensation or charge. Respondent confidentiality was maintained and responses were de-identified and aggregated prior to analyses. Initial data collection occurred from May 4, 2021, to July 12, 2021. Results: In total, 64 diabetologists/endocrinologists (D/Es) and 187 primary care physicians (PCPs) completed the full assessment within the data collection period.

When asked how many of their patients with diabetes have a prescription for glucagon, 88% of D/Es estimated <50% (and 69% estimated <20%) , 93% of PCPs estimated <50% (and 87% estimated <20%) . Conclusion: This educational research on assessment of physicians’ clinical practices yielded important insights into clinical gaps related to assessment and treatment of severe hypoglycemia in patients with diabetes. Further studies are planned to assess the effect of medical education on decreasing these clinical practice gaps.

Disclosure

A.Larkin: None. A.Le: None. J.Schrand: None.

Funding

Developed through independent educational grant from Xeris Pharmaceuticals
385-P: Effects of Ertugliflozin on Podocyte in High-Fat Diet–Induced Diabetic Kidney Disease Model, In Vivo and In Vitro
Authors: KIM HAE KYUNG , KIM YOUNGJOON , KIM RYEONG-HYEON , LEE SIWOO , YANG YURIM , PARK HYUNKI , JEON NARA , LEE MINYOUNG , LEE YONG-HO , CHA BONG-SOO , LEE HYANGKYU , LIM BEOM JIN , CHOI HOON YOUNG , KANG EUN SEOK
Published: May 2022

Early stage of diabetic kidney disease (DKD) involves loss of podocytes, consequently causing albuminuria. SGLT2 inhibitors demonstrated renoprotective effects in DKD, but the mechanism for protection in early DKD is unclear. Here, we investigated the effects of ertugliflozin in high-fat diet (HFD) -induced DKD model, in vivo and in vitro. 5-week-old male C57BL/6J mice were supplemented with HFD for 24 weeks to develop HFD-induced DKD. Ertugliflozin was administrated orally by pre-mixing with HFD for 16 weeks. We evaluated body weight, random blood glucose levels, albuminuria and glucose and insulin tolerance test were performed at 12 weeks after ertugliflozin administration. The renal cortex was collected for histologic examination and SGLT2 expression on podocytes were measured. Albuminuria was significantly decreased in ertugliflozin group compared with HFD group at 12 weeks of ertugliflozin administration (p=0.011) . Body weight, random and fasting blood glucose was not significantly different between HFD group. Glucose and insulin tolerance test showed significant improvement in ertugliflozin group compared with HFD group at 12 weeks (p=0.0004) . In immunohistochemistry studies, glomerular volume and mesangial expansion were attenuated in the ertugliflozin group by 27.6% and 27.8% respectively, compared to HFD group (p=0.002 and p=0.005, respectively) . Glomerular basement membrane thickness was decreased by 45.4% in ertugliflozin group compared to HFD group (p=0.0004) . Significant increase of SGLT2 mRNA expression by 1.6-4.8 fold after 24 hour-albumin expose was observed and SGLT2 protein was increased 1.1-1.3 fold compared to control. Ertugliflozin attenuated diabetic kidney disease in HFD-induced DKD by mitigating glomerular integrity, preserving podocyte morphology, with decreased albuminuria. Upregulation of SGLT2 in podocyte in albuminuric DKD could be suggested as possible target for renoprotective action of SGLT2 inhibitor.

Disclosure

H.Kim: None. B.Cha: None. H.Lee: None. B.Lim: None. H.Choi: None. E.Kang: None. Y.Kim: None. R.Kim: None. S.Lee: None. Y.Yang: None. H.Park: None. N.Jeon: None. M.Lee: None. Y.Lee: None.

Funding

Severance Hospital Research fund for Clinical excellence (SHRC) (C-2021-0007)
388-P: Renal ROCK2 Activity in Folic Acid-Induced Nephropathy
Authors: SEKIGUCHI KENSUKE , MATOBA KEIICHIRO , UKICHI RIKAKO , NAGAI YOSUKE , TAKEDA YUSUKE , KANAZAWA YASUSHI , UTSUNOMIYA KAZUNORI , NISHIMURA RIMEI
Published: May 2022

The small GTPase Rho and its effector Rho-kinase (ROCK) are involved in the pathogenesis of diabetic nephropathy. In chronic kidney diseases including diabetic nephropathy, tubulointerstitial fibrosis is closely related to renal outcome. We have previously reported that ROCK inhibition suppressed the progression of diabetic nephropathy in murine models. ROCK has two isoforms, ROCK1 and ROCK2. ROCK1 is known to be involved in the endocytosis of albumin in tubular epithelial cells via megalin/cubilin-dependent mechanism. On the other hand, the role of renal tubular ROCK2 has not been elucidated.In the present study, we aimed to establish the role of renal tubular ROCK2 in the pathogenesis of chronic kidney disease using a tubulointerstitial injury model known as folic acid-induced nephropathy (FAN) . Masson’s trichrome staining showed an elevated collagen deposition in the kidneys of FAN group compared with vehicle-treated group. We detected a relative upregulation of ROCK2 at protein levels in FAN group, compared with vehicle-treated group. Immunoprecipitation assay demonstrated that the kinase activity of ROCK2 relatively increased in FAN group. Based on these findings, we conclude that ROCK2 has an important contribution to tubulointerstitial fibrosis. ROCK2 may become a therapeutic target for the treatment of chronic kidney disease.

Disclosure

K.Sekiguchi: None. K.Matoba: None. R.Ukichi: None. Y.Nagai: None. Y.Takeda: None. Y.Kanazawa: None. K.Utsunomiya: None. R.Nishimura: Speaker's Bureau; Abbott Diabetes, Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Merck & Co., Inc., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi, Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Terumo Corporation.
392-P: Phase 1, Randomized, Controlled Trial of GFB-024, a Once-Monthly CB1 Inverse Agonist, in Healthy Overweight and Obese Participants and in Participants with Type 2 Diabetes Mellitus
Authors: GAICH GREGORY , BILIC SANELA , DAGON YOSSI , GUSTAFSON THOMAS , LAWLER JOHN , JOHNSON LESLIE , RUDOLPH-OWEN LORI
Published: May 2022

Evidence from nonclinical studies suggests a role of cannabinoid-1 receptor (CB1) in the development of diabetic nephropathy (DN) . Kidney CB1 expression is upregulated in podocytes and tubular cells in murine models of obesity and diabetes mellitus (DM) . Inhibition by CB1 inverse agonists has been shown to ameliorate diabetes-induced albuminuria, inhibit kidney fibrosis and inflammation, and prevent podocyte dysfunction. Mouse models of DM have shown that genetic deletion of CB1 in podocytes or proximal tubular cells protects against glomerular and tubular dysfunction.

GFB-024 is a recombinant humanized monoclonal antibody functioning as a CB1-specific inverse agonist that protects human podocytes in vitro. Targeting the CB1 pathway with GFB-024 is a potentially novel approach to protecting podocytes from injury in patients with CB1-associated DN.

In a phase 1, randomized, double-blind, placebo-controlled single ascending dose (SAD) trial, we evaluated the safety, tolerability, pharmacokinetics (PK) , and immunogenicity of GFB-024 in 38 healthy overweight and obese (BMI 25 - 40 kg/m2) participants, receiving single doses of 5 mg to 300 mg administered subcutaneously. GFB-024 was well tolerated, and there were no dose-limiting adverse effects. PK exposures achieved in the trial exceeded the estimated efficacious exposure, based on in vitro activity assays. Absorption was prolonged with flat exposure over the first 7 days, with a Tmax ranging from approximately 4-7 days. Elimination half-life was approximately 12-13 days, with exposures remaining in the estimated efficacious range at 28 days for all but the lowest dose tested.

In summary, GFB-024 was safe and well tolerated following single doses of up to 300 mg. PK analysis demonstrated potentially efficacious exposure, a prolonged absorption phase, and elimination half-life compatible with once-monthly dosing.

Disclosure

G.Gaich: Consultant; 89 bio, Inc., Employee; Goldfinch Bio, Inc. S.Bilic: Consultant; Goldfinch Bio, Inc. Y.Dagon: Employee; Goldfinch Bio, Inc. T.Gustafson: Employee; Goldfinch Bio, Inc., Janssen Pharmaceuticals, Inc. J.Lawler: Employee; Goldfinch Bio, Inc. L.Johnson: Employee; Goldfinch Bio, Inc. L.Rudolph-owen: Employee; Goldfinch Bio, Inc.
396-P: Real-Life Evaluation of Sodium–Glucose Cotransporter 2 Inhibition in Type 1 Diabetes
Authors: STOUGAARD ELISABETH BUUR , KRISTENSEN PETER L. , KIELGAST URD , ANDERSEN SR., HENRIK U. , HAMID YASMIN H. , GÆDE PETER , SØNDERGAARD ESBEN , DØRFLINGER GRY , FJELDBORG KAREN K. , HANSEN KLAVS W. , THOMSEN HENRIK H. , AL-IMARI THURAYA , RØDER MICHAEL , ROSSING PETER , PERSSON FREDERIK
Published: May 2022

Background: The indication for treatment of type 1 diabetes (T1D) with the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin has been withdrawn from the European market likely because of concern for diabetic ketoacidosis (DKA) . We aimed to calculate the incidence of DKA in people with T1D treated with SGLT2i in Denmark.

Methods: The study is based on clinical data from adults with T1D in Denmark, diagnosed according to the treating specialist and carefully selected for treatment with SGLT2i. Data were collected from nine outpatient clinics. Our National electronic health record system makes it is possible to search for a specific diagnosis both in an outpatient setting and during hospitalization, which makes the search for DKA accurate.

Results: From a population of 10.500 adults with T1D followed at the nine sites, we observed 134 people treated with SGLT2i over a total period of 222 patient years. Of them 72% were female, mean age (SD) was 51.4 (13.6) years and median duration of treatment (median, IQR) with an SGLT2i were 12.0 (6.0-29.0) months. The incidence of DKA was 0%.

Conclusion: In this retrospective observational study based on reported data from nine participating centers in Denmark in 134 people with T1D treated with SGLT2i we found that none of the participants developed DKA during the treatment.

Disclosure

E.Buur stougaard: Other Relationship; Novo Nordisk. K.W.Hansen: Advisory Panel; Abbott Diagnostics. H.H.Thomsen: Other Relationship; Boehringer Ingelheim International GmbH. T.Al-imari: None. M.Røder: None. P.Rossing: Consultant; Astellas Pharma Inc., AstraZeneca, Bayer AG, Gilead Sciences, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Speaker's Bureau; Eli Lilly and Company. F.Persson: Advisory Panel; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Research Support; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi. P.L.Kristensen: Speaker's Bureau; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi. U.Kielgast: Advisory Panel; Abbott, Eli Lilly and Company, Mundipharma, Novo Nordisk, Sanofi, Consultant; Boehringer Ingelheim International GmbH, Other Relationship; Boehringer Ingelheim International GmbH, Novo Nordisk, Novo Nordisk. H.U.Andersen: Advisory Panel; Abbott Diabetes, Stock/Shareholder; Novo Nordisk A/S. Y.H.Hamid: n/a. P.Gæde: Advisory Panel; AstraZeneca, Research Support; Novo Nordisk. E.Søndergaard: None. G.Dørflinger: None. K.K.Fjeldborg: Other Relationship; AstraZeneca.
398-P: KIM-1 and TNFR 1 and Associations with Early Diabetic Nephropathy Histology
Authors: TIAN FRANCES , PRINCE DAVID , DORIA ALESSANDRO , MAUER MICHAEL , KESTENBAUM BRYAN
Published: May 2022

Aim: GFR and urine albumin excretion (UAE) are prevailing measures used to detect and monitor diabetic nephropathy (DN) . We tested whether serum kidney injury molecule-1 (KIM-1) and tumor necrosis factor receptor-1 (TNFR1) , markers of DN progression, are associated with DN renal structural parameters in persons with TIDM.

Methods: We measured KIM-1 and TFNR1 in 285 participants from the Renin Angiotensin System Study (RASS) . Participants had T1DM for 2-20 yrs and were free of any clinical DN. Baseline iGFR and kidney biopsies were obtained. We used linear regression to estimate cross-sectional associations of markers with renal structural measures.

Results: Mean age was 30 ± yrs; mean iGFR was 125 ± 18 ml/min/1.73 m2; median UAE was 5 (IQR 4- 7) . Higher KIM-1 was associated with significantly greater mesangial fraction volume [Vv (Mes/glom) ] and the tubular atrophy (table 1) . Higher TNFR1 was associated with significantly higher Vv (Mes/glom) and glomerular basement membrane (GBM) width. Neither iGFR nor UAE were significantly associated with lesions.

Conclusion: Serum KIM-1 and TNFR1 were associated with higher values for Vv (Mes/glom) , GBM, and tubular atrophy in persons with T1DM and normal kidney function, suggesting relevance as markers of early DN structural changes prior to UAE elevation or GFR decline. KIM-1 is specific to the tubules, highlighting the importance of characterizing the natural history of tubular functions in DN.

Disclosure

F.Tian: None. D.Prince: None. A.Doria: Research Support; Novo Nordisk Foundation. M.Mauer: None. B.Kestenbaum: Consultant; Reata Pharmaceuticals, Inc.

Funding

T32
402-P: Machine Learning Approach to Evaluate the Prospective Kidney Failure Risk of the Complement Proteome in T1D
Authors: DOM ZAIPUL MD , MOON SALINA , PICKETT SARA , DILLON SIMON , NIEWCZAS MONIKA
Published: May 2022

We tested the Complement proteome’s prognostic accuracy for kidney outcomes in T1D using a machine learning (ML) approach.

Methods: This prospective cohort study comprised 193 Joslin Kidney Study subjects with T1D and an overt diabetic kidney disease at baseline followed for years. We performed urinary measurements of the Complement proteins (n=82) using aptamer proteomics. The outcomes of interest included developing end-stage kidney disease (ESKD) in or 3 years and a kidney slope. We tested biostatistical logistic regression (LR) and 7 ML models (principal component (PCA) ; decision tree: random forest (RF) and generalized boosting (GB) ; penalized regression: elastic net (EN) , lasso (LS) and ridge (RD) ; and neural network (NN)) .

Results: The LR model with the top protein had decent model accuracy (c=0.80-0.86) across the kidney outcomes, which was further improved in the ML model with proteins (PCA) . The performance of the 7 ML was comparable or higher with the best ML model being EN (AUC=0.80-0.90) . Accuracy was better for the shorter follow-up period or slope-based outcomes (Figure 1) . Models fed with 82 proteins did not much improve performance.

Conclusions: Multiple Complement proteins are strongly associated with short-to-long term kidney outcomes in T1D and offer attractive prognostic accuracy in ML models to complement biostatistical tools.

Disclosure

Z.Md dom: None. S.Moon: None. S.Pickett: None. S.Dillon: None. M.Niewczas: None.

Funding

National Institutes of Health (RO1 DK123459) Beatson FoundationHearst Foundation
404-P: Relationships among Triglyceride (TG) Concentrations across Lipoprotein Subclasses, Intraglomerular Hemodynamics, and Kidney Oxygen Availability in Adolescents with Type 1 Diabetes (T1D)
Authors: PAULEY MEGHAN E. , TOMMERDAHL KALIE L. , VINOVSKIS CARISSA , PYLE LAURA , WADWA R. PAUL , NELSON ROBERT G. , NADEAU KRISTEN J. , BJORNSTAD PETTER
Published: May 2022

TG concentrations across lipoprotein subclasses associate with diabetic kidney disease (DKD) in adults with T1D, but little is known about this relationship in youth with T1D. We evaluated cross-sectional relationships among TG concentrations across lipoprotein subclasses, intraglomerular hemodynamics, and renal oxygen availability (RO2) in youth with T1D. Glomerular filtration rate (GFR) , RO2, renal plasma flow (RPF) , afferent arteriolar resistance (RA) , efferent arteriolar resistance (RE) , intraglomerular pressure (PGLO) , and urine albumin-to-creatinine ratio (UACR) were assessed. Concentrations of lipid constituents from lipoprotein subclasses were quantified via targeted nuclear magnetic resonance spectroscopy (Nightingale Health Ltd., Helsinki, Finland) . Particle sizes for VLDL, LDL, intermediate-density lipoprotein, and HDL were measured. Fifty youth with T1D (age 16.0 ± 3.0 years, 50% female, HbA1c 8.7 ± 1.3%, T1D duration 5.7 ± 2.6 years) and 20 without T1D were included. VLDL-TG concentrations and small LDL-TG correlated with intraglomerular hemodynamic function parameters and RO2. To conclude, strong relationships were found among renal function markers and TG concentrations across lipoprotein subclasses in adolescents with T1D.

Disclosure

M.E.Pauley: None. K.L.Tommerdahl: None. C.Vinovskis: None. L.Pyle: None. R.Wadwa: Advisory Panel; Dompé, Consultant; Beta Bionics, Inc., Other Relationship; Tandem Diabetes Care, Inc., Research Support; Dexcom, Inc., Eli Lilly and Company, Tandem Diabetes Care, Inc. R.G.Nelson: None. K.J.Nadeau: None. P.Bjornstad: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Horizon Therapeutics plc, LG Chem, Lilly, Novo Nordisk, Consultant; AstraZeneca, Bristol-Myers Squibb Company.

Funding

MEP supported by NIH (T32DK063687) ; KLT supported by NIH (K23 HL159292) , Children’s Hospital Colorado Research Institute Research Scholar Award, University of Colorado Diabetes Research Center (P30 DK116073) , Ludeman Family Center for Women’s Health Research at the University of Colorado, and Dept of Pediatrics, Section of Endocrinology at University of Colorado School of Medicine; PB supported by NIDDK (RDK129211, R21 DK129720, K23 DK116720, UC DK114886, and P30 DK116073) , JDRF (2-SRA-2019-845-S-B, 3-SRA-2017-424-M-B, 3-SRA-2022-1097-M-B) , Boettcher Foundation, American Heart Association (20IPA35260142) , Ludeman Family Center for Women’s Health Research at the University of Colorado, Department of Pediatrics, Section of Endocrinology and Barbara Davis Center for Diabetes at University of Colorado School of Medicine
408-P: Fibrosis 4 Index Related to Microalbuminuria in Tibetan Patients with T2D and NAFLD
Authors: ZHANG CHENGHUI
Published: May 2022

Aim: The co-existence of type 2 diabetes (T2D) with nonalcoholic fatty liver disease (NAFLD) significantly increases the prevalence of advanced fibrosis and end-stage liver disease, as well as cardiovascular disease risk and mortality. Fibrosis 4 (FIB-4) index has been described as a non-invasive marker to detect liver fibrosis, based on several laboratory texts (AST/ALT/Platelets) . This study aimed to explore the relationship between FIB-4 index and macroalbuminuria in patients with T2D and NAFLD.

Methods: This cross-sectional utilized data in Tibetan patients with T2D and NAFLD from 2020-2021. Patients were divided into two groups based on FIB-4 index (group 1: FIB-4<1.45; group 2: FIB-4≥1.45) . Reduced eGFR was defined as eGFR <60 ml/min per 1.73 m2 and macroalbuminuria was defined as urinary albumin/creatine ≥ 300 mg/g.

Results: A total of 362 patients were recruited. Clinical characteristics of subjects were showed in Table 1. In Multiple logistic regression analysis, compared to patients with FIB-4 <1.45, those with FIB-4 ≥ 1.45 were at a 2.26-fold (95% CI:1.08-4.73) for macroalbuminuria, after adjusted for age, gender, duration of T2D, BMI, LDL-C, HbA1c and hypertension. However, FIB-4 index was not associated with reduced eGFR (OR: 2.34, 95% CI: 0.89-6.18) .

Conclusions: Our finding showed that an increase in FIB-4 index was independently associated with macroalbuminuria in T2D patients with NAFLD.

Disclosure

C.Zhang: None.
418-P: Certain Patient Subgroups with Type 2 Diabetes May Benefit from Intensive Glycemic and Blood Pressure Control from Reductions in Major Adverse Cardiovascular Events (MACE) : A Machine Learning–Based Post Hoc Analysis of ACCORD Trial Data
Authors: KIANMEHR HAMED , ZHANG PING , OSPINA NAYKKY SINGH , SHI LIZHENG , FONSECA VIVIAN , GUO JINGCHUAN , SHAO HUI
Published: May 2022

Negative or neutral treatment effects reported in many clinical trials reflect average treatment effects in the trial population and may mask heterogeneous treatment effects across patient subgroups. Machine learning (ML) methods are valuable tools to study these treatment heterogeneities. Using ML methods and data collected in the ACCORD trial, we identified patient subgroups that might benefit from intensive glycemic and blood pressure intervention. The ACCORD found that intensive glucose (A1c <6.0% vs. A1c 7.0% to 7.9%) and SBP (<120 mmHg vs. <140 mmHg) control did not significantly reduce CVD risks. We reanalyzed data from 10,251 participants from the glucose trial and 4,733 from the SBP sub-trial separately. We used Major Adverse Cardiovascular Events (MACE) as our CVD outcome. We applied causal forest (CF) and causal tree (CT) models to identify participant characteristics that modulate the effectiveness of intensive glycemic and SBP intervention from a list of 48 candidate variables (demographics, disease histories, medications, and biomarkers) at the study baseline. Compared to controls, intensive SBP intervention reduced MACE in those with normal HDL (women >55 mg/dL, men >45 mg/dL; relative risk [RR] 0.51, 95% CI: 0.34-0.74%) and those with LDL >100 mg/dL (RR: 0.74, 95% CI: 0.59-0.94) , but had no significant effects in other patient groups. Intensive glycemic control reduced MACE in those with baseline A1c <8.5% (RR: 0.79, 95% CI: 0.67-0.93) and those with glomerular filtration rate >1mL/min/1.73m2 (i.e., highest quartile; RR: 0.74, 95% CI: 0.55-0.99) ; reductions were not significant in other patient groups. Our findings may assist clinicians in developing a more precise approach to managing persons with type 2 diabetes at high risk of CVD events. Future clinical trials may be needed to confirm these findings.

Disclosure

H.Kianmehr: None. P.Zhang: None. N.Singh ospina: None. L.Shi: None. V.Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. J.Guo: None. H.Shao: Board Member; BRAVO4HEALTH, LLC.
42-LB: Distress in Living with Diabetes Links to Age, Sex, Weight, and Good Glycaemic Control
Authors: HEALD ADRIAN H. , WAHEED UNAIZA , STEDMAN MICHAEL , PAISLEY ANGELA N. , SOLOMON EMMA
Published: May 2022

Diabetes impacts on mental health. We investigated patient characteristics of those most at risk and consequences for glycaemic control.

Depression (PHQ-9) , Diabetes Distress Screening Scale (DDSS) and Quality of Life (EQ5D) on-line questionnaires were completed by people with diabetes and linked to data extracted data from responders’ clinical records. Sources of distress were also considered through evaluating sub-scales Emotional, Physician, Regimen and Interpersonal DDSS scores.

130 responses with 34% T1DM, 56% women, median age 59 (IQR47-67) years were recorded. The median scores were EQ5D=0.74 (IQR 0.64 - 0.85) UK median 0.83; DDSS=1.9 (IQR1.3-2.7) (≥2 indicates moderate distress) and PHQ9=5 (IQR2-11) (≥5 indicates depression) .

Higher DDSS/lower EQ5D5L/higher PHQ-9 within the response group were linked to female sex (DDSS 0.5/25% above median) , younger age (<50years DDSS 0.7/35% above median) , fewer years after diagnosis (<10years DDSS 0.8/40% above median) , and obesity (BMI>35 DDSS 0.6/30% above median) .

33 people with good (HbA1c≤48mmol/mol) or improving glycaemic control (HbA1c reduced by 2mmol/mol since previous reading) had higher DDSS = 2.4 versus the others = 1.9.

The link between individual DDSS and PHQ-9 scores was significant r2=0.4, while the association to EQ5D was less r2=0.11. For 30 people with history of anti-depressant medication use, DDSS was 0.9/45% above median, showing medical diagnosis confirmed self-reported distress.

DDSS scores did not significantly link to diabetes type or insulin use.

Physician related DDSS higher scores came from women, younger age, overweight, early years after diagnosis, plus history of antidepressant use. This is potentially remediable.

Level of distress is associated/maybe required in achieving and maintaining lower HbA1c. The impact on mental health of younger women/people with shorter diabetes duration should be noted when considering psychosocial intervention/behaviour change messaging.

Disclosure

A. H. Heald: None. U. Waheed: None. M. Stedman: None. A. N. Paisley: None. E. Solomon: None.