| 1. |
- Munn-Chernoff, M. A., et al.
(författare)
-
Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies
- 2021
-
Ingår i: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 26:1
-
Tidskriftsartikel (refereegranskat)abstract
- Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r(g)], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from similar to 2400 to similar to 537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r(g) = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r(g) = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r(g) = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r(gs) = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
|
|
| 2. |
- Lee, Mary R., et al.
(författare)
-
The novel ghrelin receptor inverse agonist PF-5190457 administered with alcohol: preclinical safety experiments and a phase 1b human laboratory study
- 2020
-
Ingår i: Molecular Psychiatry. - : NATURE PUBLISHING GROUP. - 1359-4184 .- 1476-5578. ; 25:2, s. 461-475
-
Tidskriftsartikel (refereegranskat)abstract
- Rodent studies indicate that ghrelin receptor blockade reduces alcohol consumption. However, no ghrelin receptor blockers have been administered to heavy alcohol drinking individuals. Therefore, we evaluated the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD) and behavioral effects of a novel ghrelin receptor inverse agonist, PF-5190457, when co-administered with alcohol. We tested the effects of PF-5190457 combined with alcohol on locomotor activity, loss-of-righting reflex (a measure of alcohol sedative actions), and on blood PF-5190457 concentrations in rats. Then, we performed a single-blind, placebo-controlled, within-subject human study with PF-5190457 (placebo/0 mg b.i.d., 50 mg b.i.d., 100 mg b.i.d.). Twelve heavy drinkers during three identical visits completed an alcohol administration session, subjective assessments, and an alcohol cue-reactivity procedure, and gave blood samples for PK/PD testing. In rats, PF-5190457 did not interact with the effects of alcohol on locomotor activity or loss-of-righting reflex. Alcohol did not affect blood PF-5190457 concentrations. In humans, all adverse events were mild or moderate and did not require discontinuation or dose reductions. Drug dose did not alter alcohol concentration or elimination, alcohol-induced stimulation or sedation, or mood during alcohol administration. Potential PD markers of PF-5190457 were acyl-to-total ghrelin ratio and insulin-like growth factor-1. PF-5190457 (100 mg b.i.d.) reduced alcohol craving during the cue-reactivity procedure. This study provides the first translational evidence of safety and tolerability of the ghrelin receptor inverse agonist PF-5190457 when co-administered with alcohol. PK/PD/behavioral findings support continued research of PF-5190457 as a potential pharmacological agent to treat alcohol use disorder.
|
|
| 3. |
- Prahalad, P., et al.
(författare)
-
Hemoglobin A1c trajectories in the first 18 months after diabetes diagnosis in the SWEET diabetes registry
- 2022
-
Ingår i: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X .- 1399-5448. ; 23:2, s. 228-236
-
Tidskriftsartikel (refereegranskat)abstract
- Aim: A majority of youth with type 1 diabetes do not meet recommended hemoglobin A1c (HbA1c) targets. The SWEET diabetes registry is a multi-national registry of youth with diabetes. We used data from this registry to identify characteristics associated with glycemic control. Methods: Patients in the SWEET diabetes registry with at least one HbA1c value within 10 days of diagnosis and three follow up measurements in the first 18 months of diagnosis were included (similar to 10% of the SWEET diabetes registry). Locally weighted scatterplot smoothing was used to generate curves of HbA1c. Wilcoxon, Kruskal-Wallis, chi 2-tests were used to calculate differences between groups. Results: The mean HbA1c of youth in the SWEET diabetes registry is highest at diagnosis and lowest between months 4 and 5 post-diabetes diagnosis. HbA1c continues to increase steadily through the first 18 months of diagnosis. There are no differences in HbA1c trajectories based on sex or use of diabetes technology. Youth in North America/Australia/New Zealand had the highest HbA1c throughout the first 18 months of diagnosis. The trajectory of youth from countries with nationalized health insurance was lower than those countries without nationalized health insurance. Youth from countries with the highest gross domestic product (GDP) had the highest HbA1c throughout the first 18 months of diagnosis. Conclusions: In this subset of patients, the trajectory of youth from countries with nationalized health insurance was lower than those countries without nationalized health insurance. High GDP and high use of technology did not seem to protect from a higher trajectory.
|
|
| 4. |
- Gerhardsson, P., et al.
(författare)
-
The SWEET Project 10-Year Benchmarking in 19 Countries Worldwide Is Associated with Improved HbA1c and Increased Use of Diabetes Technology in Youth with Type 1 Diabetes
- 2021
-
Ingår i: Diabetes Technology & Therapeutics. - : Mary Ann Liebert Inc. - 1520-9156 .- 1557-8593. ; 23:7
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: The international SWEET registry (NCT04427189) was initiated in 2008 to improve outcomes in pediatric diabetes. A 10-year follow-up allowed studying time trends of key quality indicators in 22 centers from Europe, Australia, Canada, and India in youth with type 1 diabetes (T1D). Methods: Aggregated data per person with T1D <25 years of age were compared between 2008-2010 and 2016-2018. Hierarchic linear and logistic regression models were applied. Models were adjusted for gender, age-, and diabetes duration groups. Results: The first and second time periods included 4930 versus 13,654 persons, 51% versus 52% male, median age 11.3 [Q1; Q3: 7.9; 14.5] versus 13.3 [9.7; 16.4] years, and T1D duration 2.9 [0.8; 6.4] versus 4.2 [1.4; 7.7] years. The adjusted hemoglobin A1C (HbA1c) improved from 68 (95% confidence interval [CI]: 66-70) to 63 (60; 65) mmol/mol (P<0.0001) or 8.4 (95% CI: 8.2-8.6) to 7.9 (7.6; 8.1) % (P<0.0001). Across all age groups, HbA1c was significantly lower in pump and sensor users. Severe hypoglycemia declined from 3.8% (2.9; 5.0) to 2.4% (1.9; 3.1) (P<0.0001), whereas diabetic ketoacidosis events increased significantly with injection therapy only. Body mass index-standard deviation score also showed significant improvements 0.55 (0.46; 0.64) versus 0.42 (0.33; 0.51) (P<0.0001). Over time, the increase in pump use from 34% to 44% preceded the increase in HbA1c target achievement (<53mmol/mol) from 21% to 34%. Conclusions: Twice yearly benchmarking within the SWEET registry was associated with significantly improved HbA1c on a background of increasing pump and sensor use for 10 years in young persons with T1D.
|
|
