Risk factors and outcomes associated with recurrent autoimmune hepatitis following liver transplantation

Background & Aims: Autoimmune hepatitis can recur after liver transplantation (LT), though the impact of recurrence on patient and graft survival has not been well characterized. We evaluated a large, international, multicenter cohort to identify the probability and risk factors associated with recurrent AIH and the association between recurrent disease and patient and graft survival.Methods: We included 736 patients (77% female, mean age 42 +/- 1 years) with AIH who underwent LT from January 1987 through June 2020, among 33 centers in North America, South America, Europe and Asia. Clinical data before and after LT, biochemical data within the first 12 months after LT, and immunosuppression after LT were analyzed to identify patients at higher risk of AIH recurrence based on histological diagnosis.Results: AIH recurred in 20% of patients after 5 years and 31% after 10 years. Age at LT <= 42 years (hazard ratio [HR] 3.15; 95% CI 1.22-8.16; p = 0.02), use of mycophenolate mofetil post-LT (HR 3.06; 95% CI 1.39-6.73; p = 0.005), donor and recipient sex mismatch (HR 2.57; 95% CI 1.39-4.76; p = 0.003) and high IgG pre-LT (HR 1.04; 95% CI 1.01-1.06; p = 0.004) were associated with higher risk of AIH recurrence after adjusting for other confounders. In multivariate Cox regression, recurrent AIH (as a time-dependent covariate) was significantly associated with graft loss (HR 10.79, 95% CI 5.37-21.66, p <0.001) and death (HR 2.53, 95% CI 1.48-4.33, p = 0.001).Conclusion: Recurrence of AIH following transplant is frequent and is associated with younger age at LT, use of mycophenolate mofetil post-LT, sex mismatch and high IgG pre-LT. We demonstrate an association between disease recurrence and impaired graft and overall survival in patients with AIH, highlighting the importance of ongoing efforts to better characterize, prevent and treat recurrent AIH.Lay summary: Recurrent autoimmune hepatitis following liver transplant is frequent and is associated with some recipient features and the type of immunosuppressive medications use. Recurrent autoimmune hepatitis negatively affects outcomes after liver transplantation. Thus, improved measures are required to prevent and treat this condition. (C) 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Energy resolution of a silicon detector with the RX64 ASIC designed for X-ray imaging

Results from a silicon microstrip detector coupled to the RX64 ASIC are presented. The system is capable of single photon counting in digital X-ray imaging, with foreseen applications to dual energy mammography and angiography. The main features of the detecting system are low noise (operation with threshold as low as E4 keV is possible), good spatial resolution (a pixel of 100 mm 300 mm when oriented edge-on) and good counting rate capability (up to one million counts per channel with a maximum rate of about 200 kHz per channel). The energy resolution of the system, as obtained with several fluorescence X-ray lines, is described

A silicon stripdetector coupled to the RX64 ASIC for X-ray diagnostic imaging

Firstresultsfromasiliconmicrostripdetectorwith100mmpitchcoupledtotheRX64ASICarepresented. The system is capable of single photon counting in digital X-ray imaging, with possible applications to dual energy mammography and angiography. The main features of the detecting system are low noise, good spatial resolution and high counting rate capability. The energy resolution and the conversion efficiency of the system are discussed, based on results obtained with fluorescence X-ray sources and quasi-monochromatic X-ray beams in the 8–36 keV energy range, with strips being either orthogonal or parallel to the incoming X-rays. We present also preliminary imaging results obtained with a plexiglass phantom with tiny cylindrical cavities filled with iodate solution, simulating patient vessels; in this case the X-ray beam has two components, respectively below and above the iodine K- edge at 33:17 keV

X-ray imaging with a silicon microstrip detector coupled to the RX64 ASIC

A single photon counting X-ray imaging system, with possible applications to dual energy mammography and angiography, is presented. A silicon microstrip detector with 100 μm pitch strips is coupled to RX64 ASICs, each of them including 64 channels of preamplifier, shaper, discriminator and scaler. The system has low noise, good spatial resolution and high counting rate capability. Results on energy resolution have been obtained with a fluorescence source and quasi-monochromatic X-rays beams. Preliminary images obtained with an angiographic phantom are presented

Results about imaging with silicon strips for angiography and mammography

We present results obtained with a single photon counting system consisting of 384 silicon microstrips of 100 micron pitch equipped with 6 RX64 ASICs. The ASIC includes a charge preamplifier, a shaper, a discriminator and a 20‐bit counter for each of its 64 channels. The energy resolution of the system has been measured in the range from 8 keV to 32 keV using fluorescence X‐ray lines from several targets, using either an Am‐241 source or an X‐ray tube. Then, the efficiency of the system has been determined using the specially developed quasi‐monochromatic X‐ray beams in the energy range 18–36 KeV. Good efficiency has been obtained in the edge‐on configuration, which is more suitable for the intended applications. The spatial resolution of the system has been verified using a special microfocus X‐ray tube equipped with capillaries. Finally, images of angiographic and mammographic test objects have been obtained with dual energy X‐ray beams and have then been processed with the dual energy subtraction technique. In particular, the contrast for the angiographic test object has been evaluated for different concentrations of an iodate solution injected into 1 mm and 2 mm diameter vessels. Further developments, including a double threshold version of the ASIC, are also discussed

GSK‐3 inhibition by adenoviral FRAT1 overexpression is neuroprotective and induces Tau dephosphorylation and β‐catenin stabilisation without elevation of glycogen synthase activity

Glycogen synthase kinase 3 (GSK-3) has previously been shown to play an important role in the regulation of apoptosis. However, the nature of GSK-3 effector pathways that are relevant to neuroprotection remains poorly defined. Here, we have compared neuroprotection resulting from modulation of GSK-3 activity in PC12 cells using either selective small molecule ATP-competitive GSK-3 inhibitors (SB-216763 and SB-415286), or adenovirus overexpressing frequently rearranged in advanced T-cell lymphomas 1 (FRAT1), a protein proposed as a negative regulator of GSK-3 activity towards Axin and Glycogen synthase kinase 3 (GSK-3) has previously been shown to play an important role in the regulation of apoptosis. However, the nature of GSK-3 effector pathways that are relevant to neuroprotection remains poorly defined. Here, we have compared neuroprotection resulting from modulation of GSK-3 activity in PC12 cells using either selective small molecule ATP-competitive GSK-3 inhibitors (SB-216763 and SB-415286), or adenovirus overexpressing frequently rearranged in advanced T-cell lymphomas 1 (FRAT1), a protein proposed as a negative regulator of GSK-3 activity towards Axin and β-catenin. Our data demonstrate that cellular overexpression of FRAT1 is sufficient to confer neuroprotection and correlates with inhibition of GSK-3 activity towards Tau and β-catenin, but not modulation of glycogen synthase (GS) activity. By comparison, treatment with SB-216763 and SB-415286 proved more potent in terms of neuroprotection, and correlated with inhibition of GSK-3 activity towards GS in addition to Tau and β-catenin-catenin. Our data demonstrate that cellular overexpression of FRAT1 is sufficient to confer neuroprotection and correlates with inhibition of GSK-3 activity towards Tau and β-catenin, but not modulation of glycogen synthase (GS) activity. By comparison, treatment with SB-216763 and SB-415286 proved more potent in terms of neuroprotection, and correlated with inhibition of GSK-3 activity towards GS in addition to Tau and β-cateni