Mycophenolate Interruption Restores Anti-SARS-CoV-2 Vaccine Immunogenicity in Unresponsive Liver Transplant Recipients

Background & aims: The fourth dose of anti-SARS-CoV-2 vaccine slightly improved the humoral response among previously seronegative liver transplant (LT) recipients. Mycophenolate (MMF) treatment worsens the vaccination response. This study aimed to evaluate whether temporary MMF interruption might improve the immunogenicity of the fourth anti-SARS-CoV-2 BNT16b2 vaccine dose in nonresponsive LT recipients. Methods: LT recipients negative for anti-spike glycoprotein-specific immunoglobulin G receptor-binding domain (s-RBD) antibodies after the third vaccine dose were enrolled. Anti-SARS-CoV-2 spike-specific T-cell responses were measured before and 2 months following the fourth vaccine dose, and anti-SARS-CoV-2 s-RBD antibodies also 6 months thereafter. MMF was suspended two weeks before and after vaccination. Results: Five LT recipients were enrolled. After a mean of 78 days after vaccination, all patients tested positive for anti-SARS-CoV-2 s-RBD antibodies. The mean antibody titer was 8944 UI/mL. The positive antibody response was maintained during a mean of 193 days of follow-up. Three patients developed a positive T-cell response. Two patients (one positive for T-cell response) developed a self-limited SARS-CoV-2 infection. Conclusions: Suspending MMF prior to the fourth dose of the anti-SARS-CoV-2 mRNA vaccine seems feasible and safe. This procedure could restore vaccine-induced immunogenicity in a large portion of previously nonresponsive LT recipients

Baseline Predictors of the Long-Term Insufficient Biochemical Response in Patients with Autoimmune Hepatitis: A Single Center Experience

The treatment response criteria in autoimmune hepatitis (AIH) have been recently updated. This study aimed to assess treatment responses in 39 (16 males) patients with AIH confirmed by histology. Prednisone added to azathioprine or mycophenolate was the most frequent first-line treatment. Serum alanine aminotransferase (ALT) levels were periodically checked for a median of 45 months. Eight (20.5%) patients presented 4 weeks non-response (NR). Baseline lower multiples of ALT above the upper normal limit (UNL) (p = 0.005), Ishak liver fibrosis score > 3 (p = 0.029), and less frequent confluent necrosis > 2 (p 100 strongly predicted CBR failure (p = 0.003) at a follow-up greater than 12 months. In conclusion, the absence of cirrhosis and a ≥50% UNL decrease in serum ALT levels were independent predictors for CBR. A baseline GLUCRE score may help identify patients maintaining longer CBR

Vitamin D binding protein gene polymorphisms and baseline vitamin D levels as predictors of antiviral response in chronic hepatitis C

Vitamin D deficiency seems to predict the unsuccessful achievement of sustained viral response (SVR) after anti-viral treatment in hepatitis C virus (HCV) difficult to treat genotypes. Vitamin D binding protein (GC) gene polymorphisms are known to influence vitamin D levels. This study was performed to assess whether the interaction between basal circulating vitamin D and the GC polymorphism plays a role in influencing the rate of anti viral responses in patients affected by chronic hepatitis C. Two hundred six HCV patients treated with a combination therapy of PEGinterferon plus ribavirin were retrospectively evaluated. GC rs7041 G>T, GC rs4588 C>A and IL- 28B rs12979860 C>T polymorphisms were genotyped. Frequencies of GC rs7041 G>T and rs4588 C>A polymorphisms were: G/G=64 (31.1%), G/T=100 (48.5%), T/T=42 (20.4%) and C/C=108 (52.4%), C/A=84 (40.8%), A/A=14 (6.8%). Patients were divided into those carrying 653 major alleles (WT+: G-C/G-C, G-C/T-C, G-C/G-A, N=100) and the remaining (WT-: G-C/T-A, T-A/T-C, T-A/T-A, T-C/T-C, N=106). Four groups were identified: vitamin D 6420 ng/mL and WT-, vitamin D 6420 and WT+, vitamin D>20 and WT-, vitamin D>20 and WT+. In difficult to treat HCV genotypes the proportion of patients achieving SVR significantly increased with a linear trend from the first to the last group: 6/25 (24.0%), 9/24 (37.5%), 12/29 (41.4%), 19/29 (65.5%) (p=0.003). At multivariate analysis having basal vitamin D >20 ng/mL plus the carriage of GC WT+ was found to be an independent predictor of SVR (O.R. 4.52, p=0.015). Conclusions: in difficult to treat HCV genotypes, simultaneous pre treatment normal serum vitamin D levels and the carriage of GCglobulin wild type isoform strongly predicts the achievement of SVR after PEG-interferon plus ribavirin antiviral therapy. Page 3 of 28 Hepatolog

Trends in chronic hepatitis B virus infection in Italy over a 10-year period: Clues from the nationwide PITER and MASTER cohorts toward elimination

Objectives: The study measures trends in the profile of patients with chronic hepatitis B virus linked to care in Italy. Methods: A cross-sectional, multicenter, observational cohort (PITER cohort) of consecutive patients with hepatitis B surface antigen (HBsAg) over the period 2019-2021 from 46 centers was evaluated. The reference was the MASTER cohort collected over the years 2012-2015. Standard statistical methods were used. Results: The PITER cohort enrolled 4583 patients, of whom 21.8% were non-Italian natives. Compared with those in MASTER, the patients were older and more often female. The prevalence of hepatitis B e antigen (HBeAg) declined (7.2% vs 12.3; P <0.0001) and that of anti-hepatitis D virus (HDV) remained stable (9.3% vs 8.3%). In both cohorts, about 25% of the patients had cirrhosis, and those in the PITER cohort were older. HBeAg-positive was 5.0% vs 12.6% (P <0.0001) and anti-HDV positive 24.8% vs 17.5% (P <0.0017). In the logistic model, the variables associated with cirrhosis were anti-HDV-positive (odds ratio = 10.08; confidence interval 7.63-13.43), age, sex, and body mass index; the likelihood of cirrhosis was reduced by 40% in the PITER cohort. Among non-Italians, 12.3% were HBeAg-positive (vs 23.4% in the MASTER cohort; P <0.0001), and 12.3% were anti-HDV-positive (vs 11.1%). Overall, the adherence to the European Association for the Study of the Liver recommendations for antiviral treatment increased over time. Conclusion: Chronic hepatitis B virus infection appears to be in the process of becoming under control in Italy; however, HDV infection is still a health concern in patients with cirrhosis and in migrants

A holistic evaluation of patients with chronic Hepatitis D virus (HDV) infection enrolled in the Italian PITER-B and delta cohort

Background and Aims: We aimed to characterize the epidemiologic and comorbidities profiles of patients with chronic Hepatitis D (CHD) followed in clinical practice in Italy and explored their interferon (IFN) eligibility. Methods: This was a cross-sectional study of the PITER cohort consisting of consecutive HBsAg-positive patients from 59 centers over the period 2019-2023. Multivariable analysis was performed by logistic regression model. Results: Of 5492 HBsAg-positive enrolled patients, 4152 (75.6%) were screened for HDV, 422 (10.2%) were anti-HDV positive. Compared with HBsAg mono-infected, anti-HDV positive patients were more often younger, non-Italians, with a history of drug use, had elevated alanine transaminase (ALT), cirrhosis, or hepatocellular carcinoma (HCC). Compared with Italians, anti-HDV positive non-Italians were younger (42.2% age ≤ 40 years vs. 2.1%; P < 0.001), more often females (males 43.0% vs. 68.6%; P < 0.001) with less frequent cirrhosis and HCC. HDV-RNA was detected in 63.2% of anti-HDV-positive patients, who were more likely to have elevated ALT, cirrhosis, and HCC. Extrahepatic comorbidities were present in 47.4% of anti-HDV positive patients and could affect the eligibility of IFN-containing therapies in at least 53.0% of patients in care. Conclusions: CHD affects young, foreign-born patients and older Italians, of whom two-thirds had cirrhosis or HCC. Comorbidities were frequent in both Italians and non-Italians and impacted eligibility for IFN

New organ allocation criteria in liver transplantation

Summary. The organ allocation modality in the liver transplant represents a fundamental step for the correct success of the transplantation procedure. The practical effects deriving from the adoption of the organ allocation models do not imply only clinical repercussions but also concern important ethical aspects. Alongside the general principles of fairness, justice and transparency, the organ allocation models should be aimed at providing for each patient who waits for an organ, the possibility of accessing it, preserving and maximizing the outcome of the transplant in terms of survival and quality of life. Balancing successfully the clinical and ethical aspects in an allocation model is particularly difficult and probably not completely feasible. In this brief review, the general principles governing the different models of organ allocation in liver transplantation are addressed. A particular description of the decision-making process that led to the sharing in Italy of a new allocation model based on the concept of the transplant benefit is illustrated. In this model we have tried to combine the two fundamental principles that for many years have guided the choice of allocation models, respectively based on the criteria of urgency and utility

13 kA Superconducting Busbars Manufacturing Process

In the LHC, the superconducting Main Bending magnets and Quadrupole magnets are series-connected electrically in different excitation circuits by means of superconducting busbars, carrying a maximum current of 13 kA. These superconducting busbars consist of a superconducting Rutherford cable thermally and electrically coupled to a copper section all along the length. The function of the copper section is essentially to provide an alternative path for the magnet current in case of resistive transition. The production of these components was originally outsourced. The decision to import the technology at CERN led to a global re-engineering of the standard process. Although based on the procedures adopted during the LHC construction, a few modifications and improvements have been implemented, profiting of the experience gained in the last few years. This document details the manufacturing process of the 13 kA busbars as it is actually performed at CERN, emphasizing the new solutions adopted during the first months of production

Challenges and future developments in liver transplantation

Liver transplantation (LTLT) has become the treatment of choice for a wide range of liver diseases in both adult and pediatric patients. Until recently, the largest proportion of LTLT in adults, were performed in patients with hepatitis C (HCV) related cirrhosis. The recent availability of safe and effective direct antiviral agents to cure HCV infection in almost all patients whatever the HCV genotype and severity of liver disease, will reduce the need for LTLT in this category of recipients. Thus, it is presumed that in the next 1 to 2 decades HCV related liver disease will diminish substantially, whereas non-alcoholic steato-hepatitis (NAS H) will correspondingly escalate as an indication for LTLT. The greatest challenges facing LTLT remain the limited supply of donor organs, and the need for chronic immunosuppression, which represent the true obstacles to the greater application and durable success of the LTLT procedure. This review aimed to highlight, in different sections, the main open issues and future developments in LTLT. These will be focused to explore current and future strategies to maximize the use of limited organs, to offer an update on potential new approaches to immunosuppression and to imagine new indications for LTLT when the number of patients awaiting transplants for HCV related liver disease is reduced