Implementation of Epic Beaker Clinical Pathology at Stanford University Medical Center.

OBJECTIVES: To provide an account of implementation of the Epic Beaker 2014 clinical pathology module at Stanford University Medical Center and highlight strengths and weaknesses of the system. METHODS: Based on a formal selection process, Stanford selected Epic Beaker to replace Sunquest as the clinical laboratory information system (LIS). The rationale included integration between the LIS and already installed Epic electronic medical record (EMR), reduction in the number of systems and interfaces, and positive patient identification (PPID). The build was significantly customized and included a first of its kind Epic-to-Epic interface. This was due to the clinical laboratory serving two hospitals (pediatric and adult) with independent instances of Epic. RESULTS: Test turnaround times showed improvement from historical baselines, mostly because of the implementation of PPID. PPID also resulted in significant reduction in mislabeled specimens. CONCLUSIONS: Epic 2014 Beaker clinical pathology is a viable LIS with adequate functionality for a large academic center. Strengths include PPID and integration with the EMR. Integration provides laboratory users with ready access to the patient\u27s relevant clinical history to assist releasing of results and gives physician and nurse providers sophisticated add-on ordering and specimen collection workflows. Areas that could use further development include specimen aliquoting, quality control reporting, and maintenance tools

Alkaline ceramidase 2 is essential for the homeostasis of plasma sphingoid bases and their phosphates.

Sphingosine-1-phosphate (S1P) plays important roles in cardiovascular development and immunity. S1P is abundant in plasma because erythrocytes-the major source of S1P-lack any S1P-degrading activity; however, much remains unclear about the source of the plasma S1P precursor, sphingosine (SPH), derived mainly from the hydrolysis of ceramides by the action of ceramidases that are encoded by 5 distinct genes, acid ceramidase 1 ( ASAH1)/ Asah1, ASAH2/ Asah2, alkaline ceramidase 1 ( ACER1)/ Acer1, ACER2/ Acer2, and ACER3/ Acer3, in humans/mice. Previous studies have reported that knocking out Asah1 or Asah2 failed to reduce plasma SPH and S1P levels in mice. In this study, we show that knocking out Acer1 or Acer3 also failed to reduce the blood levels of SPH or S1P in mice. In contrast, knocking out Acer2 from either whole-body or the hematopoietic lineage markedly decreased the blood levels of SPH and S1P in mice. Of interest, knocking out Acer2 from whole-body or the hematopoietic lineage also markedly decreased the levels of dihydrosphingosine (dhSPH) and dihydrosphingosine-1-phosphate (dhS1P) in blood. Taken together, these results suggest that ACER2 plays a key role in the maintenance of high plasma levels of sphingoid base-1-phosphates-S1P and dhS1P-by controlling the generation of sphingoid bases-SPH and dhSPH-in hematopoietic cells.-Li, F., Xu, R., Low, B. E., Lin, C.-L., Garcia-Barros, M., Schrandt, J., Mileva, I., Snider, A., Luo, C. K., Jiang, X.-C., Li, M.-S., Hannun, Y. A., Obeid, L. M., Wiles, M. V., Mao, C. Alkaline ceramidase 2 is essential for the homeostasis of plasma sphingoid bases and their phosphates. FASEB J 2018 Jun; 32(6):3058-3069

Alkaline Ceramidase 3 Deficiency Results in Purkinje Cell Degeneration and Cerebellar Ataxia Due to Dyshomeostasis of Sphingolipids in the Brain

<div><p>Dyshomeostasis of both ceramides and sphingosine-1-phosphate (S1P) in the brain has been implicated in aging-associated neurodegenerative disorders in humans. However, mechanisms that maintain the homeostasis of these bioactive sphingolipids in the brain remain unclear. Mouse alkaline ceramidase 3 (Acer3), which preferentially catalyzes the hydrolysis of C_18:1-ceramide, a major unsaturated long-chain ceramide species in the brain, is upregulated with age in the mouse brain. Acer3 knockout causes an age-dependent accumulation of various ceramides and C_18:1-monohexosylceramide and abolishes the age-related increase in the levels of sphingosine and S1P in the brain; thereby resulting in Purkinje cell degeneration in the cerebellum and deficits in motor coordination and balance. Our results indicate that Acer3 plays critically protective roles in controlling the homeostasis of various sphingolipids, including ceramides, sphingosine, S1P, and certain complex sphingolipids in the brain and protects Purkinje cells from premature degeneration.</p></div

Correction: Alkaline Ceramidase 3 Deficiency Results in Purkinje Cell Degeneration and Cerebellar Ataxia Due to Dyshomeostasis of Sphingolipids in the Brain

<p>Correction: Alkaline Ceramidase 3 Deficiency Results in Purkinje Cell Degeneration and Cerebellar Ataxia Due to Dyshomeostasis of Sphingolipids in the Brain</p

Generation of Acer3 null mouse.

<p><b>A</b>. Acer3 targeting strategy. The Acer3 gene consists of 11 exons (empty rectangles with the numerals inside). Exon 8 of the Acer3 gene was replaced by the <i>Neo</i> resistant gene cassette upon homologous recombination. <b>B</b>. Southern blot analyses of WT ES cells or ES cells from an Acer3-targeted ES clone. Genomic DNA was digested with EcoRV, resolved on a 0.8% agarose gel, transferred to a nitrocellulose membrane, which was labeled with a radioactive probe (P) corresponding to the region upstream of Exon 8 as shown in Panel A. <b>C</b>. PCR-based genotyping of Acer3^+/+, Acer3^+/-, and Acer3^-/- mice. DNA was isolated from mouse tail biopsies and subjected to PCR analyses using the PCR primer pairs (F1 and B1 or F1 and B2) as shown in Panel A. The image in C represents the PCR product patterns of the three genotypes, Acer3^+/+, Acer3^+/-, and Acer3^-/-.</p

Establishing an Updated Core Domain Set for Studies in Juvenile Idiopathic Arthritis: A Report from the OMERACT 2018 JIA Workshop

The current Juvenile Idiopathic Arthritis (JIA) Core Set used in randomized controlled trials (RCT) and longitudinal observational studies (LOS) was developed without the input of patients/parents. At the Outcome Measures in Rheumatology (OMERACT) 2016, a special interest group voted to reconsider the core set, incorporating broader input. We describe subsequent work culminating in an OMERACT 2018 plenary and consensus voting

Acer3 knockout impairs motor coordination and balance capabilities in mice.

<p><b>A</b>-<b>D</b>. Rotarod tests for motor coordination. Acer3^+/+ and Acer3^-/- mice at 6W, 4M, 6M, 8M, or 12M of age were subjected to rotarod tests under 3 task difficulties—10, 15, and 20 rpm, respectively. Hindlimb step patterns in a representative Acer3^+/+ and Acer3^-/- mouse at 8M of age at 20 rpm are displayed in D. Note that the hindpaws of Acer3^-/- mice, but not those of Acer3^+/+ mice slipped off the rod. <b>E</b>-<b>H</b>. Beam walking tests for motor coordination and balance capabilities. Acer3^+/+ and Acer3^-/- mice at 6W or 8M of age were subjected to beam walking tests under two task difficulties. The average of three trials were quantitatively analyzed for time to traverse the beam (E), walking distance (F), and foot-slips of hindpaws (G). Patterns of hindpaw contacting the beam during walking in a representative 8-month-old Acer3^+/+ and Acer3^-/- mouse are displayed in H. Note the foot-slips for both beam walking conditions in the Acer3^-/- mouse. The data in A, B, C, E, F, and G represent mean values ± SD, n = 5–8. n.s., not significant.</p

Acer3 knockout does not affect myelination.

<p><b>A</b>-<b>D</b>. Cerebellar sections of Acer3^+/+ and Acer3^-/- mice at 8M of age were stained with Luxol fast blue (A). The myelin width indicated by black arrowhead was measured in the images of the cerebellar sections stained with Luxol fast blue (B). MBP protein levels in cerebellar homogenates were analyzed by immunoblotting (C) and quantified (D). <b>E</b>. Electron microscopy of the ultrastructure of myelin sheaths in the cerebellum of Acer3^+/+ and Acer3^-/- mice at 8M of age. The image in A or E represents the results from one of four mice in each group. The data in B and D represent mean values ± SD, n = 4.</p

Acer3 knockout does not have any major defect in mouse development and fertility.

<p><b>A</b>. The average litter size of Acer3^+/+ or Acer3^-/- interbreeding mice (n = 4 litters per breeding pair) from 4 pairs of interbreeding mice. <b>B</b>. The average body weight of Acer3^+/+ or Acer3^-/- mice at 6 weeks (6W), 4 months (4M), 6 months (6M), 8 months (8M), and 12 months (12M) of age, n = 5–10 per age group. Data in A and B represent mean values ± SD.</p