Fumarylacetoacetate Hydrolase Knock-out Rabbit Model for Hereditary Tyrosinemia Type 1.

Hereditary tyrosinemia type 1 (HT1) is a severe human autosomal recessive disorder caused by the deficiency of fumarylacetoacetate hydroxylase (FAH), an enzyme catalyzing the last step in the tyrosine degradation pathway. Lack of FAH causes accumulation of toxic metabolites (fumarylacetoacetate and succinylacetone) in blood and tissues, ultimately resulting in severe liver and kidney damage with onset that ranges from infancy to adolescence. This tissue damage is lethal but can be controlled by administration of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), which inhibits tyrosine catabolism upstream of the generation of fumarylacetoacetate and succinylacetone. Notably, in animals lacking FAH, transient withdrawal of NTBC can be used to induce liver damage and a concomitant regenerative response that stimulates the growth of healthy hepatocytes. Among other things, this model has raised tremendous interest for the in vivo expansion of human primary hepatocytes inside these animals and for exploring experimental gene therapy and cell-based therapies. Here, we report the generation of FAH knock-out rabbits via pronuclear stage embryo microinjection of transcription activator-like effector nucleases. FAH-/- rabbits exhibit phenotypic features of HT1 including liver and kidney abnormalities but additionally develop frequent ocular manifestations likely caused by local accumulation of tyrosine upon NTBC administration. We also show that allogeneic transplantation of wild-type rabbit primary hepatocytes into FAH-/- rabbits enables highly efficient liver repopulation and prevents liver insufficiency and death. Because of significant advantages over rodents and their ease of breeding, maintenance, and manipulation compared with larger animals including pigs, FAH-/- rabbits are an attractive alternative for modeling the consequences of HT1.Wellcome Trus

The ENIGMA sports injury working group - an international collaboration to further our understanding of sport-related brain injury

Sport-related brain injury is very common, and the potential long-term effects include a wide range of neurological and psychiatric symptoms, and potentially neurodegeneration. Around the globe, researchers are conducting neuroimaging studies on primarily homogenous samples of athletes. However, neuroimaging studies are expensive and time consuming, and thus current findings from studies of sport-related brain injury are often limited by small sample sizes. Further, current studies apply a variety of neuroimaging techniques and analysis tools which limit comparability among studies. The ENIGMA Sports Injury working group aims to provide a platform for data sharing and collaborative data analysis thereby leveraging existing data and expertise. By harmonizing data from a large number of studies from around the globe, we will work towards reproducibility of previously published findings and towards addressing important research questions with regard to diagnosis, prognosis, and efficacy of treatment for sport-related brain injury. Moreover, the ENIGMA Sports Injury working group is committed to providing recommendations for future prospective data acquisition to enhance data quality and scientific rigor

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Evaluating the use of lecture recordings and their impact on exam performance for PharmD students

Class of 2023 Abstract and PosterSpecific Aims: To quantitatively measure the relationship between students’ final grades and Panopto time streamed, times accessed, and days accessed during the year for Self-Care Therapeutics (PHPR 812) and Pharmacotherapeutics I (PHPR 860A). Secondarily, evaluate the correlation between each students’ individual exam grades and the number of times Panopto was accessed 4 days before each exam. Methods: This descriptive, observational, retrospective study for the 2021-2022 school year collected de-identified Panopto usage reports of first-year pharmacy students at the University of Arizona College of Pharmacy, along with final course grades and individual exam grades for PHPR 812 and PHPR 860A. The Pearson correlation coefficient (r) was used to measure the relationship between Panopto use and academic performance with r>0.8 or <-0.8 as unremarkable. A p-value <0.05 was considered statistically significant. Results: There were 144 students in PHPR 812 and 140 students in PHPR 860A included in the analysis. There was a statistically significant weak correlation between the number of times Panopto was accessed for PHPR 860A and the final course grade (r = -0.19, p=0.03). Exams 2 and 3 for PHPR 812 also showed statistically significant weak correlations between the number of times Panopto was accessed within 4 days of the exams and the exam grades (r = 0.2, p = 0.01; r = 0.23, p = 0.01). Conclusions: Panopto use was neither associated with benefit nor harm to students’ final class and individual exam grades. The days accessed prior to each exam also demonstrated no established relationship.This item is part of the Pharmacy Student Research Projects collection, made available by the College of Pharmacy and the University Libraries at the University of Arizona. For more information about items in this collection, please contact Jennifer Martin, Librarian and Clinical Instructor, Pharmacy Practice and Science, [email protected]

Lifestyle-Related Factors, Obesity, and Incident Microalbuminuria: The CARDIA (Coronary Artery Risk Development in Young Adults) Study

BACKGROUND: Modifiable lifestyle-related factors are associated with risk of coronary heart disease and may also influence kidney disease risk. STUDY DESIGN: Community-based prospective cohort study. SETTING & PARTICIPANTS: 2354 African-American and white participants ages 28–40 years, without baseline microalbuminuria or estimated glomerular filtration rate <60 ml/min/1.73 m(2) recruited from four U.S. centers: Birmingham AL, Chicago IL, Minneapolis MN, and Oakland CA. FACTORS: Current smoking, physical activity, fast food habits, obesity, and diet quality, which was based on 8 fundamental components of the Dietary Approaches to Stop Hypertension (DASH) diet, including increased intake of fruits, vegetables, low-fat dairy products, whole grains, nuts and legumes, and reduced intake of sodium, sugar sweetened beverages, and red and processed meats. OUTCOMES & MEASUREMENTS: Spot urine albumin-creatinine ratios (ACRs) were obtained at baseline (1995–96) and 3 5-year follow-up examinations (5, 10, and 15 years follow-up). Incident microalbuminuria was defined as presence of race and sex-adjusted ACR ≥25 mg/g at 2 or more of the successive follow-up examinations. RESULTS: Over the 15-year follow-up period, 77 individuals (3.3%) developed incident microalbuminuria. After multivariable adjustment, poor diet quality (OR, 2.0; 95% CI, 1.1–3.4) and obesity (OR, 1.9; 95% CI, 1.1–3.3) were significantly associated with microalbuminuria; current smoking (OR, 1.6; 95% CI, 0.9–2.8) was associated with microalbuminuria although the CI crossed 1.0. Neither low physical activity (OR, 1.0; 95% CI, 0.5–1.8) nor fast food consumption (OR, 1.2; 95% CI, 0.7–2.3) were associated with microalbuminuria. Compared to individuals with no unhealthy lifestyle-related factors (poor diet quality, current smoking and obesity), adjusted odds of incident microalbuminuria were 131%, 273%, and 634% higher for presence of 1 (OR, 2.3; 95% CI, 1.3–4.3), 2 (OR, 3.7; 95% CI, 1.8–7.7), and 3 (OR, 7.3; 95% CI, 2.1–26.1) unhealthy lifestyle-related factors. LIMITATIONS: Self-reported dietary history and physical activity, low number of outcomes. CONCLUSIONS: Consuming an unhealthy diet and obesity are associated with incident microalbuminuria

Altered lateralization of the cingulum in deployment‐related traumatic brain injury: An ENIGMA military‐relevant brain injury study

Traumatic brain injury (TBI) in military populations can cause disruptions in brain structure and function, along with cognitive and psychological dysfunction. Diffusion magnetic resonance imaging (dMRI) can detect alterations in white matter (WM) microstructure, but few studies have examined brain asymmetry. Examining asymmetry in large samples may increase sensitivity to detect heterogeneous areas of WM alteration in mild TBI. Through the Enhancing Neuroimaging Genetics Through Meta-Analysis Military-Relevant Brain Injury working group, we conducted a mega-analysis of neuroimaging and clinical data from 16 cohorts of Active Duty Service Members and Veterans (n =&nbsp;2598). dMRI data were processed together along with harmonized demographic, injury, psychiatric, and cognitive measures. Fractional anisotropy in the cingulum showed greater asymmetry in individuals with deployment-related TBI, driven by greater left lateralization in TBI. Results remained significant after accounting for potentially confounding variables including posttraumatic stress disorder, depression, and handedness, and were driven primarily by individuals whose worst TBI occurred before age 40. Alterations in the cingulum were also associated with slower processing speed and poorer set shifting. The results indicate an enhancement of the natural left laterality of the cingulum, possibly due to vulnerability of the nondominant hemisphere or compensatory mechanisms in the dominant hemisphere. The cingulum is one of the last WM tracts to mature, reaching peak FA around 42 years old. This effect was primarily detected in individuals whose worst injury occurred before age 40, suggesting that the protracted development of the cingulum may lead to increased vulnerability to insults, such as TBI