Cholangiocyte organoids can repair bile ducts after transplantation in the human liver.

Organoid technology holds great promise for regenerative medicine but has not yet been applied to humans. We address this challenge using cholangiocyte organoids in the context of cholangiopathies, which represent a key reason for liver transplantation. Using single-cell RNA sequencing, we show that primary human cholangiocytes display transcriptional diversity that is lost in organoid culture. However, cholangiocyte organoids remain plastic and resume their in vivo signatures when transplanted back in the biliary tree. We then utilize a model of cell engraftment in human livers undergoing ex vivo normothermic perfusion to demonstrate that this property allows extrahepatic organoids to repair human intrahepatic ducts after transplantation. Our results provide proof of principle that cholangiocyte organoids can be used to repair human biliary epithelium

Improving PBL in Empowering Meta cognitive Skill of Students

Abstract Objective: Problem-Based Learning (PBL) is a potential constructivist learning strategy that empowers students’ Meta cognitive skill. PBL focuses on problem, involves thinking activity to solve problems, and correlates to cognitive function of students. Methods: The implementation of PBL reveals various benefits, but there are also some weaknesses in this learning strategy. Thus, it is necessary to implement a certain learning strategy that can cover the PBL weaknesses, such as Reading, Questioning, and Answering (RQA) learning strategy. RQA is a new learning strategy developed based on a fact that almost all students do not read the next lecture materials, causing failure of learning strategy planned and finally the students’ comprehension becomes low. RQA is also potential to empower students’ Meta cognitive skill. Findings: The integration of RQA and PBL learning strategy is called PBL-RQA learning strategy. This study was a quasi-experimental study designed to compare the effect of PBL, RQA, and PBL-RQA learning strategies on the students’ Meta cognitive skill of Faculty of Mathematics and Science, State University of Makassar. Application: The results of the study showed that the potency of PBL learning strategy in empowering the students’ Meta cognitive skill has been increased by integrating it to RQA learning strategy. The meta cognitive skill mean score of the students taught by PBL-RQA learning strategy was 21% higher than that of the students taught by PBL and 26.9% higher than that of the students taught by RQA learning strategy. Keywords: Answering, Meta Cognitive Skill, Problem-Based Learning, Questioning, Reading, PBL-RQ

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Regulator of G-Protein Signaling 16 Is a Negative Modulator of Platelet Function and Thrombosis

© 2019 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. Background: Members of the regulator of G-protein signaling (RGS) family inhibit G-protein coupled receptor signaling by modulating G-protein activity. In platelets, there are 3 different RGS isoforms that are expressed at the protein level, including RGS16. Recently, we have shown that CXCL12 regulates platelet function via RGS16. However, the role of RGS16 in platelet function and thrombus formation is poorly defined. Methods and Results: We used a genetic knockout mouse model approach to examine the role(s) of RGS16 in platelet activation by using a host of in vitro and in vivo assays. We observed that agonist-induced platelet aggregation, secretion, and integrin activation were much more pronounced in platelets from the RGS16 knockout (Rgs16−/−) mice relative to their wild type (Rgs16+/+) littermates. Furthermore, the Rgs16−/− mice had a markedly shortened bleeding time and were more susceptible to vascular injury–associated thrombus formation than the controls. Conclusions: These findings support a critical role for RGS16 in regulating hemostatic and thrombotic functions of platelets in mice. Hence, RGS16 represents a potential therapeutic target for modulating platelet function

Arhgef1 Plays a Vital Role in Platelet Function and Thrombogenesis

© 2019 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. Background: Platelets are the cellular mediators of hemostasis and thrombosis, and their function is regulated by a number of molecular mediators, such as small GTPases. These small GTPases are themselves regulated by guanine nucleotide exchange factors such as Arhgefs, several of which are found in platelets, including the highly expressed Arhgef1. However, the role of Arhgef1 in platelets has not yet been investigated. Methods and Results: We employed mice with genetic deletion of Arhgef1 (ie, Arhgef1−/−) and investigated their platelet phenotype by employing a host of in vivo and in vitro platelet assays. Our results indicate that Arhgef1−/− mice had prolonged carotid artery occlusion and tail bleeding times. Moreover, platelets from these mice exhibited defective aggregation, dense and α granule secretion, αIIbβ3 integrin activation, clot retraction and spreading, in comparison to their wild-type littermates. Finally, we also found that the mechanism by which Arhgef1 regulates platelets is mediated in part by a defect in the activation of the RhoA–Rho-associated kinase axis, but not Rap1b. Conclusions: Our data demonstrate, for the first time, that Arhgef1 plays a critical role in platelet function, in vitro and in vivo

The JUUL E-Cigarette Elevates the Risk of Thrombosis and Potentiates Platelet Activation

© The Author(s) 2020. Background: Smoking is the main preventable cause of death in the United States and worldwide and is associated with serious cardiovascular health consequences, including thrombotic diseases. Recently, electronic cigarettes (e-cigarettes) and, in particular JUUL, have attained wide popularity among smokers, nonsmokers, pregnant females, and even the youth, which is alarming. Interestingly, there is/are no information/studies regarding the effect of JUUL on cardiovascular diseases, specifically in the context of modulation of platelet activation. Thus, it is important to discern the cardiovascular disease health risks associated with JUUL. Methods and Results: We used a passive e-vape vapor inhalation system where C57BL/6J mice (10-12 weeks old) were exposed to JUUL e-cigarette vape. Menthol flavored JUUL pods containing 5% nicotine by weight were used as the e-liquid. Mice were exposed to a total of 70 puffs daily for 2 weeks; 3-second puff duration, and 25-second puff interval. The effects of JUUL relative to clean air were analyzed, on mouse platelet function in vitro (eg, aggregation) and in vivo (eg, FeCl3-induced carotid artery injury thrombosis model). Our results indicate that short-term exposure to JUUL e-cigarette causes hyperactivation of platelets and shortens the thrombus occlusion as well as hemostasis/bleeding times, relative to clean air (medians of 14 vs. 200 seconds, P \u3c.01 and 35 vs. 295 seconds, P \u3c.001, respectively). Conclusion: Our findings document—for the first time—that short-term exposure to the JUUL e-cigarette increases the risk of thrombotic events, in part by modulating platelet function, such as aggregation and secretion, in mice

Untersuchung von Moduln mit transparenter Waermedaemmung an der Testfassade des ISE

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