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BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of cirrhosis in the USA. OBJECTIVES: We aimed to determine the time to develop hepatic events in patients with NAFLD and develop a simple model to identify patients at risk for hepatic decompensation. DESIGN: Retrospective cohort study. PATIENTS: Seven hundred patients with NAFLD met inclusion criteria for the study. Patients were divided into model construction (n = 450) and validation (n = 250) cohorts. MAIN MEASURES: Demographic, clinical, and laboratory variables were gathered at the time of diagnosis of NAFLD. Kaplan-Meier analysis determined the time to development of hepatic events from initial diagnosis. A time-to-event prediction model was established in the model construction cohort using the multivariate Cox proportional hazards model and was then internally validated. KEY RESULTS: Forty-nine (7%) patients developed hepatic events at a mean duration of 6.2 ± 4.2 years from initial diagnosis. Kaplan-Meier probability of developing a hepatic event at 5-, 10-, and 12-year intervals was 4.8%, 10.6%, and 11.3%, respectively. Age, presence of diabetes, and platelet count were identified as significant variables to predict hepatic events. NAFLD decompensation risk score was developed as “age × 0.06335 + presence of diabetes (yes = 1, no = 0) × 0.92221 − platelet count × 0.01522” to predict the probability of hepatic decompensation. Risk score model had an area under the curve of 0.89 (95% CI = 0.92, 0.86) and it performed well in both the validation (0.91, 0.87–0.94) and the overall cohort (0.89, 0.87–0.91). CONCLUSIONS: A significant proportion of patients with NAFLD developed hepatic decompensation. We have provided a simple, objective model to help identify “at-risk” patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11606-020-05725-1) contains supplementary material, which is available to authorized users.

© 2019 Elsevier B.V. This manuscript version is made available under the CC-BY-NC-ND 4.0 license: http://creativecommons.org/licenses/by-nc-nd/4.0/ This author accepted manuscript is made available following 12 month embargo from date of publication (January 2019) in accordance with the publisher’s archiving policy, In forensic DNA analysis there is valid interest in the reliability of the interpretation reported. Reliability, in part but not fully, relates to the scientific concepts of repeatability, reproducibility, and accuracy. Before attempting to address repeatability and reproducibility, and the challenge in context of determining accuracy in context, we give a brief summary of the current process that leads to the reported result.

Vi ønsket å finne ut hva pedagogisk entreprenørskap er i skolen. Dette gjorde vi ved å foreta tekstanalyse av den generelle delen av LK06, samt støttedokumenter. Vi utførte også åpent intervju av to lærere og fire elever fra mellomtrinnet. I vår analyse av Generelle delen fant vi ut at begrepet pedagogisk entreprenørskap ikke blir nevnt direkte, men i stedet gjennom ord som kan hevdes å bety det samme. Den generelle delen av LK06 fremmer indirekte pedagogisk entreprenørskap gjennom arbeidsmetoder der det vektlegges aktiv og reflekterende læring. Fra intervju med lærerne fant vi ut at de ikke hadde kjennskap til begrepet pedagogisk entreprenørskap, eller regjeringens satsing omkring entreprenørskap i skolen. Lærerne formidlet at de ikke praktiserte pedagogisk entreprenørskap, men at samtale og gruppearbeid var sentralt i deres undervisning. Gruppearbeid kan ansees som en liten del av pedagogisk entreprenørskap, og vi kan da trekke en slutning på at pedagogisk entreprenørskap ble benyttet til en viss grad. Elevene ytret et sterkt ønske om en mer variert undervisning i stedet for det de opplevde som tradisjonelle arbeidsoppgaver. Slik sett ønsket elevene pedagogisk entreprenørskap velkommen uten at heller ikke de brukte begrepet. Elevenes ønsker samsvarer dermed med intensjoner i Generell del om pedagogisk entreprenørskap, men det er mindre samsvar mellom Generell del og lærerens praksis.

Aims Grapefruit juice inhibits CYP3A4 in the intestinal wall leading to a reduced intestinal first pass metabolism and thereby an increased oral bioavailability of certain drugs. For example, it has been shown that the oral bioavailability of midazolam, a CYP3A4 substrate, increased by 52% in healthy subjects after ingestion of grapefruit juice. However, this interaction has not been studied in patients with impaired liver function. Accordingly, the effect of grapefruit juice on the AUC of midazolam and the metabolite α-hydroxymidazolam was studied in patients with cirrhosis of the liver. Methods An open randomized two-way crossover study was performed. Ten patients (3 females, 7 males) with liver cirrhosis based on biopsy or clinical criteria participated. Six patients had a Child-Pugh score of A, one B and three C. Tap water (200 ml) or grapefruit juice were consumed 60 and 15 min before midazolam (15 mg) was administered orally. Plasma samples were analysed for midazolam and α-hydroxymidazolam. Results Grapefruit juice increased the AUC of midazolam by 106% (16, 197%) (mean (95% confidence interval)) and the AUC of the metabolite α-hydroxymidazolam decreased to 25% (12, 37%) (P

International audience; Many infectious agents utilize CD46 for infection of human cells, and therapeutic applications of CD46-binding viruses are now being explored. Besides mediating internalization to enable infection, binding to CD46 can directly alter immune function. In particular, ligation of CD46 by antibodies or by measles virus can prevent activation of T cells by altering T-cell polarity and consequently preventing the formation of an immunological synapse. Here, we define a mechanism by which CD46 reorients T-cell polarity to prevent T-cell receptor signaling in response to antigen presentation. We show that CD46 associates with lipid rafts upon ligation, and that this reduces recruitment of both lipid rafts and the microtubule organizing centre to the site of receptor cross-linking. These data combined indicate that polarization of T cells towards the site of CD46 ligation prevents formation of an immunological synapse, and this is associated with the ability of CD46 to recruit lipid rafts away from the site of TCR ligation.

Grapefruit juice inhibits CYP3A4 in the intestinal wall leading to a reduced intestinal first pass metabolism and thereby an increased oral bioavailability of certain drugs. For example, it has been shown that the oral bioavailability of midazolam, a CYP3A4 substrate, increased by 52% in healthy subjects after ingestion of grapefruit juice. However, this interaction has not been studied in patients with impaired liver function. Accordingly, the effect of grapefruit juice on the AUC of midazolam and the metabolite alpha-hydroxymidazolam was studied in patients with cirrhosis of the liver.An open randomized two-way crossover study was performed. Ten patients (3 females, 7 males) with liver cirrhosis based on biopsy or clinical criteria participated. Six patients had a Child-Pugh score of A, one B and three C. Tap water (200 ml) or grapefruit juice were consumed 60 and 15 min before midazolam (15 mg) was administered orally. Plasma samples were analysed for midazolam and alpha-hydroxymidazolam.Grapefruit juice increased the AUC of midazolam by 106% (16, 197%) (mean (95% confidence interval)) and the AUC of the metabolite alpha-hydroxymidazolam decreased to 25% (12, 37%) (P0.05 for both). The ratio of the AUCs of the metabolite alpha-hydroxymidazolam to midazolam decreased from 0.77 (0.46, 1.07) to 0.11 (0.05, 0.19) (P0.05). t(1/2) remained unaltered for both drug and metabolite. Midazolam C(max), t(max), and alpha-hydroxymidazolam t(max) increased, but these changes were not statistically significant, whereas C(max) of the metabolite decreased to 30% (14, 47%) (P0.05).A marked interaction between oral midazolam and grapefruit juice was found and the data are consistent with a reduced first-pass metabolism of midazolam. This is likely to occur at the intestinal wall inhibition of CYP3A4 activity by grapefruit juice. These results indicate that patients with liver cirrhosis are more dependent on the intestine for metabolism of CYP3A4 substrates than subjects with normal liver function.

Tests were performed to check if the dissected cells are affectively retrieved into the collection tubes, if cross contamination could occur if cells were collected from multiple slides containing cells of differing origin, and if the work environment surfaces contained any DNA that may cause a contamination risk. A less than ideal laboratory environment, sampling different cells from multiple slides, and inadequate cleaning procedures may negatively affect cell collection and/or increase contamination risk. Recommendations are made to assist in limiting the risk of contamination while using laser microdissection to collect cells for forensic DNA profiling.

SummaryT cell shape is dictated by the selective recruitment of molecules to different regions of the cell (polarity) and is integral to every aspect of T cell function, from migration to cytotoxicity. This study describes a mechanism for the regulation of T cell polarity. We show that T cells contain a network of asymmetrically distributed proteins with the capacity to dictate the subcellular localization of both cell surface receptors and morphological determinants in T cells. Proteins from the Scribble, Crumbs3, and Par3 complexes, previously shown to regulate epithelial polarity, were polarized in T cells containing either uropods or immunological synapses. Reduction in Scribble expression prevented the polarization of cell surface receptors and prevented morphological changes associated with uropod formation, migration, and antigen presentation. By dynamically coordinating molecular distribution throughout the T cell, this network provides a mechanism by which T cell function and polarity are linked.