Letter to the editors

We read with interest the study by Manzia et al. [1] onthe effect of maintenance of mycophenolate mofetil(MMF) monotherapy on progression of recurrent hepati-tis C virus (HCV) after liver transplantation.The authors concluded: MMF ''monotherapy may cur-rently represent the preferred immunosuppressive alterna-tive for the long-term management of liver transplantrecipients with HCV infection''. However, we believe thatthey should exert great caution in coming to this conclu-sion, as their results [1] have not been properly evaluatedwithin the context of the complete picture of the pub-lished literature on the subject.Our group recently published a review on the role ofMMF and azathioprine in liver transplantation withregard to acute rejection, renal dysfunction and HCVrecurrence [2]. Considering HCV recurrence, we showedthat between 2001 and 2007, 17 studies evaluated MMFand HCV recurrence; among these, only two studies [3,4]found a decreased severity of HCV recurrence with MMFand one of these had no multivariate analysis [3] – citedby Manzia et al. Nine studies (reported in reference 2)documented similar severity of HCV recurrence; however,six studies [5–10] showed increased severity of HCVrecurrence, but only one of these [10] was cited byManzia et al.Therefore, the study by Manzia et al. [1] representsonly the third study out of 18 (17%) showing a beneficialtherapeutic effect of MMF on HCV progression after livertransplantation, whereas 33% shows a deleterious effect.For this reason, in omitting to cite this literature, Maniaet al. have gone against the available evidence in statingthat MMF is the preferred immunosuppressive alternativefor long-term regimen in patients transplanted for HCV-related cirrhosis.Moreover, although Manzia et al. [1] showed in theirpatient cohort a positive association between a favorableeffect of MMF monotherapy on the progression of hepa-tic fibrosis in HCV liver transplant patients, there are sev-eral methodological issues. There was no multivariateanalysis evaluating MMF with respect to fibrosis progres-sion. This is especially important, as the study was retro-spective and nonrandomized and with only 15 patientsper arm. Although other studies have also been retrospec-tive and nonrandomized [2], several have included multi-variate analyses.Thus, overall, the current published evidence for MMFwith respect to the severity of fibrosis and HCV recur-rence does not suggest a beneficial effect. If anything, apotential adverse effect is shown as we pointed out in ourreview [2], although we acknowledged then, and now thatthe evidence is weak.Giacomo Germani

Political ecology of health in the Land of Fires: a hotspot of environmental crimes in the south of Italy

Environmental crimes, if they are perceived as victimless, have not received the appropriate governmental response and have been frequently ranked low on the law enforcement priority list, punished with lenient or no administrative sanctions. This has contributed to an underestimation of the immediate consequences of environmental crimes, which can go undetected for lengthy periods. On the contrary, the mismanagement and illegal trafficking of waste in the Land of Fires, an area in the Campania region in the South of Italy, has been experienced as a 'victimful' crime. Using a political ecology of health approach, and integrating qualitative and quantitative methods, we investigate how the perception of being a victim of waste-related environmental crimes has been magnified by evidence of serious disease outcomes . Health concerns have become a central issue in the resurgence of grassroots movements against waste mismanagement in Campania

Predicting acute cellular rejection after liver transplantation: form liver function test to immune monitoring

In recent years, the main end point of immunosuppressive therapy after liver transplantation has moved from the prevention of acute cellular rejection (ACR) toward the preservation of long-term graft function and prevention of immunosuppression-related side effects. This approach requires an optimal management of immunosuppressive therapy according to patient risk factors. However, the concentration of immunosuppressive drugs in the serum of patients, which is generally used as a surrogate for the level of immunosuppression, does not provide information about the magnitude of suppression of the immune system. Therefore a reliable marker for the development of ACR, or to predict patients who could tolerate reduced immunosuppression, would be crucial for improving post-transplant management of liver transplanted patients. The aims of the studies presented in this thesis were: 1) to assess the incidence of ACR after liver transplantation, to identify potential risk factors for ACR, and to evaluate the impact of ACR and its histological severity on outcomes; 2) to evaluate the role of liver function tests and blood eosinophil count as potential biomarkers for ACR after liver transplantation, with special attention on prediction of histologically proven moderate and severe ACR; 3) to evaluate the expression of specific immunological markers for ACR in patients before and after liver transplantation. The results of the studies showed that patient and graft survival at 1, 5 and 10 years after liver transplantation were not different with respect to presence or absence of ACR. Only untreated moderate/severe ACR was associated with increased death/graft loss using adjusted Cox regression analysis, whereas mild ACR, whether treated or not, had no effect. With regards to the evaluation of potential markers of ACR, despite peripheral eosinophilia was not sufficiently predictive of moderate/severe ACR, the delta in eosinophil count between the first and second biopsies was the only independent predictor of histological improvement, irrespective of whether bolus steroids were used. Lastly, we demonstrated that the increased expression of C28 and C38 on both CD4+ and CD8+ T cells and the increased levels of IL-17. These alterations of immune system could be used routinely in clinical practice to assess the immune status of liver transplanted patients and to properly manage immunosuppressive therap

Immunosuppression and HCV recurrence after liver transplantation

SummaryHCV related liver disease is the most common indication for liver transplantation. Recurrence of HCV infection is universal and has a substantial impact on patient and graft survival. Immunosuppression is a major factor responsible for the accelerated recurrence and compressed natural history of recurrent HCV infection. Accumulating experience has provided data to support certain strategies for immunosuppressive regimens.From the available evidence, more severe recurrence results from repeated bolus corticosteroid therapy and anti-lymphocyte antibodies used to treat rejection. Low dose and slow tapering of steroids are better than high dose maintenance and/or rapid tapering. Recent meta-analyses favour steroid-free regimens but these are complicated to interpret as the absence of steroids may simply represent less immunopotency.There is no difference in HCV recurrence between tacrolimus and cyclosporine regimens, but tacrolimus increases graft and patient survival in HCV transplanted patients. There may be a beneficial effect of maintenance azathioprine given for 6months or longer. There is no conclusive evidence for benefit of mycophenolate and interleukin-2 receptor blockers. Few data are available for mTOR inhibitors. Better evidence is needed to establish the optimal immunosuppressive regimen for HCV recipients and more randomized trials should be performed

Hepatitis C virus related cirrhosis decreased as indication to liver transplantation since the introduction of direct-acting antivirals: A single-center study

AIM: To evaluate waiting list (WL) registration and liver transplantation (LT) rates in patients with hepatitis C virus (HCV)-related cirrhosis since the introduction of direct-acting antivirals (DAAs). METHODS: All adult patients with cirrhosis listed for LT at Padua University Hospital between 2006-2017 were retrospectively collected using a prospectively-updated database; patients with HCV-related cirrhosis were divided by indication for LT [dec-HCV vs HCV/ hepatocellular carcinoma (HCC)] and into two interval times (2006-2013 and 2014-2017) according to the introduction of DAAs. For each patient, indications to LT, severity of liver dysfunction and the outcome in the WL were assessed and compared between the two different time periods. For patients receiving DAA-based regimens, the achievement of viral eradication and the outcome were also evaluated. RESULTS: One thousand one hundred and ninty-four [male (M)/female (F): 925/269] patients were included. Considering the whole cohort, HCV-related cirrhosis was the main etiology at the time of WL registration (490/1194 patients, 41%). HCV-related cirrhosis significantly decreased as indication to WL registration after DAA introduction (from 43.3% in 2006-2013 to 37.2% in 2014-2017, P = 0.05), especially amongst dec-HCV (from 24.2% in 2006-2013 to 15.9% in 2014-2017, P = 0.007). Even HCV remained the most common indication to LT over time (289/666, 43.4%), there was a trend towards a decrease after DAAs introduction (from 46.3% in 2006-2013 to 39% in 2014-2017, P = 0.06). HCV patients (M/F: 43/11, mean age: 57.7 \ub1 8 years) who achieved viral eradication in the WL had better transplant-free survival (log-rank test P = 0.02) and delisting rate (P = 0.002) than untreated HCV patients. CONCLUSION: Introduction of DAAs significantly reduced WL registrations for HCV related cirrhosis, especially in the setting of decompensated cirrhosis

Courage and representations of death in patients who are waiting for a liver transplantation

Context: In the last decade, a wide literature has highlighted the importance of religiosity as support of severe illnesses, especially the oncological ones, and in the end of life. In the field of the liver transplant there is a lack of similar research. This article aims to bridge this gap and presents an exploratory study on the relationships between fear of death, courage and religiosity among patients who wait for liver transplant. Method: Sixty-two participants awaiting a liver transplant were interviewed with regard to their quality of life, religiosity, ontological representations and fear of death, courage and fear of intervention, donor-related thoughts. The following instruments were utilized: a specific interview; the Short Form Health Survey (SF-36); the Testoni Death Representation Scale (TDRS) and the Courage Measure. Results: Patients reporting higher levels of fear for intervention showed less courage and were more likely to avoid the surgery. They also tended to be non-believers, to have a lower quality of life, and to represent death as an absolute annihilation. Conclusions: The less death was represented as a passage, the stronger the avoidance behaviour and the fear of transplant were. Since it is possible to develop a positive thought about death, the study underlined how the spiritual support could be useful to manage fear of transplantation

Liver transplantation for viral hepatitis in 2015

Liver transplantation (LT) is a life-saving treatment for patients with end-stage liver disease and for patients with liver cell cancer related to liver disease. Acute and chronic liver diseases related to hepatitis viruses are between the main indications for liver transplantation. The risk of viral reinfection after transplantation is the main limiting factor in these indications. Before the availability of antiviral prophylaxis, hepatitis B virus (HBV) recurrence was universal in patients who were HBV DNA-positive before transplantation. The natural history of recurrent HBV was accelerated by immunosuppression, and it progressed rapidly to graft failure and death. Introduction of post-transplant prophylaxis with immunoglobulin alone first, and associated to antiviral drugs later, drastically reduced HBV recurrence, resulting in excellent long-term outcomes. On the contrary, recurrence of hepatitis C is the main cause of graft loss in most transplant programs. Overall, patient and graft survival after LT for hepatitis C virus (HCV)-associated cirrhosis is inferior compared with other indications. However, successful pretransplant or post transplant antiviral therapy has been associated with increased graft and overall survival. Until recently, the combination of pegylated interferon and ribavirin was the standard of care for the treatment of patients with chronic hepatitis C. Highly active antiviral compounds have been developed over the past decade, thanks to new in vitro systems to study HCV entry, replication, assembly, and release

Management of bacterial infection in the liver transplant candidate

Bacterial infection (BI) is a common cause of impairment of liver function in patients with cirrhosis, especially in the liver transplant candidates. These patients share an immunocompromised state and increased susceptibility to develop community and hospital-acquired infections. The changing epidemiology of BI, with an increase of multidrug resistant strains, especially in healthcare-associated settings, represents a critical issue both in the waiting list and in the post-operative management. This review focused on the role played by BI in patients awaiting liver transplantation, evaluating the risk of drop-out from the waiting list, the possibility to undergo liver transplantation after recovery from infection or during a controlled infection

Hemodynamic Evaluation of Nonselective \u3b2-Blockers in Patients with Cirrhosis and Refractory Ascites

BACKGROUND:Nonselective \u3b2-blockers (NSBB) have been associated with increased incidence of paracentesis-induced circulatory dysfunction (PICD) and reduced survival in patients with cirrhosis and refractory ascites. AIM:To prospectively evaluate a hemodynamic response to NSBB in cirrhotics listed for liver transplantation with refractory ascites undergoing large volume paracentesis (LVP). METHODS:Patients with cirrhosis and refractory ascites, with an indication to start NSBB in primary prophylaxis for variceal bleeding, were enrolled. During two consecutive LVP, while being, respectively, off and on NSBB, cardiac output (CO), systemic vascular resistances (SVR), peripheral vascular resistances (PVR), and plasma renin activity (PRA) were noninvasively assessed. RESULTS:Seventeen patients were enrolled, and 10 completed the study. Before NSBB introduction, SVR (1896 to 1348\u2009dyn\ub7s\ub7cm-5; p = 0.028) and PVR (47 to 30\u2009mmHg\ub7min\ub7dl\ub7ml-1; p = 0.04) significantly decreased after LVP, while CO showed an increasing trend (3.9 to 4.5\u2009l/m; p = 0.06). After NSBB introduction, LVP was not associated with a significant increase in CO (3.4 to 3.8\u2009l/m; p = 0.13) nor with a significant decrease in SVR (2002 versus 1798\u2009dyn\ub7s\ub7cm-5; p = 0.1). Incidence of PICD was not increased after NSBB introduction. CONCLUSION:The negative inotropic effect of NSBB was counterbalanced by a smaller decrease of vascular resistances after LVP, probably due to splanchnic \u3b22-blockade. This pilot study showed that NSBB introduction may be void of detrimental hemodynamic effects after LVP in cirrhotics with refractory ascites

Human-Centered Design of a Collaborative Robotic System for the Shoe-Polishing Process

Demand for automated processes in the manufacturing industry is now shifting toward flexible, human-centered systems that combine productivity and high product quality, thus combining the advantages of automated and robotic systems with the high-value-added skills of operators and craftsmen. This trend is even more crucial for small and medium-sized enterprises operating in the “Made in Italy” fashion industry. The paper presents the study, simulation, and preliminary testing of a collaborative robotic system for shoe polishing that can reduce manual labor by limiting it to the finishing stage of the process, where the aesthetic result is fully achieved, with a benefit also in terms of ergonomics for the operator. The influence of process parameters and design solutions are discussed by presenting preliminary test results and providing hints for future developments