[Cirrhotic cardiomyopathy ­ Clinically fact or academic curiosity? Review. Part 3: treatment] / Cardiomiopatía cirrótica ­ ¿Realidad clínica o simple curiosidad académica? Revisión.

Hepatic transplantation (HT) is the standard of care of end-stage liver disease with Cirrhotic Cardiomyopathy (CCM), but medical treatment with combination of diuretics and non-selective beta blockers are important before and after that. Owing to its particular pathophysiology unlike another etiologies of heart failure, in CCM angiotensin-converting enzyme inhibitors (ACEI), angiotensin II type I receptor blockers (ARB), and angiotensin receptor neprilysin inhibitor (ARNI) are not recommended. Transjugular intrahepatic porto-systemic shunt (TIPS) has indications in CMM but its potential benefits and risks must be considered and more researh is necessary. HT is a demanding therapy but the most effective one, and showed improvement in QTc, diastolic and systolic dysfunction; in recent decades, in spite of more severe ill patients (more severe MELD score), survival has improved significantly due to better surgical techniques, intensive care, immunosupresive drugs, and images.

El tratamiento de la enfermedad hepática terminal con Cardiomiopatía Cirrótica (CMC) es el trasplante hepático (TH), sin embargo el tratamiento médico con la combinación de diuréticos y beta bloqueantes no selectivos antes y después tienen un rol importante. A diferencia de la insuficiencia cardíaca de otras etiologías, los inhibidores de la enzima convertidora (IECA), los bloqueadores del receptor de angiotensina 2 (ARA-2) o los inhibidores del receptor de angiotensina y de neprilisina (ARNI) no se recomiendan debido a la fisiopatología particular de la CMC. El shunt porto-sistémico intrahepático transyugular (Transjugular intrahepatic porto-systemic shunt: TIPS) tiene sus indicaciones con posibles beneficios y riesgos pero más estudios son necesarios en la CMC. El TH es la opción más eficaz y puede revertir el QTc del ECG y la disfunción diastólica y sistólica; en las últimas décadas, a pesar del aumento de la complejidad en los pacientes (mayor score MELD), con la mejoría de la técnica quirúrgica, cuidados intensivos, drogas inmunosupresoras y diagnóstico por imágenes la sobrevida ha mejorado significativamente.

[Cirrhotic cardiomyopathy ­ Clinically fact or academic curiosity? Review. Part 2: ECG, functional tests, images, biomarkers, screening for coronary heart disease and differentianting diagnosis] / Cardiomiopatía cirrótica ­ ¿Realidad clínica o simple curiosidad académica? Revisión. Parte 2: ECG, pruebas funcionales, estudios con imágenes, biomarcadores, screening para enfermedad coronaria y diagnósticos diferenciales.

The diagnosis of Cirrhotic Cardiomyopathy is based on severe hepatic cirrosis with deterioration of cardiac function without previous cardiopathy, but this is subclinical during a long time. In this second part we review the non-invasive diagnostic methods and their prognostic value in patients with or without hepatic transplant, from ECG to cardiac images of magnetic resonance.

El diagnóstico de Cardiomiopatía Cirrótica está basado en la presencia de cirrosis hepática avanzada con alteraciones de la función cardíaca sin cardiopatía pre-existente, pero en gran parte de su evolución natural ésta es subclínica. Por ello son imprescindibles los estudios complementarios no invasivos para confirmar el diagnóstico y su rol pronóstico en pacientes con o sin trasplante hepático. En esta segunda parte revisamos los métodos de diagnóstico desde el ECG hasta las imágenes de resonancia magnética cardíaca.

[Cirrhotic cardiomyopathy ­ Clinically fact or academic curiosity? Review: Part 1: definition, epidemiology, pathology and clinical manifestations] / Cardiomiopatía cirrótica ­ ¿Realidad clínica o simple curiosidad académica? Revisión. Parte 1: definición, epidemiología, anatomía patológica y clínica

Severe cirrhosis affecting myocardial function provokes a syndrome called Cirrhotic Cardiomyopathy, defined as cardiac disfunction associated with hepatic cirrhosis in the absence of other known cardiac disease. The prevalence is variable according different groups of investigation owing to the latent or subclinical course until a stressful situation unmask it such as surgery, hemorrhage, infection, hepatic transplant or transjugular intrahepatic porto-systemic shunt. We aimed to review the definition, pathology, pathophysiology, clinical manifestations, diagnostic criteria, images, clinical relevance, pharmacological treatment and hepatic transplantation.

La cirrosis avanzada puede provocar alteraciones miocárdicas que constituyen el síndrome de Cardiomiopatía Cirrótica definido como la disfunción cardíaca asociada con cirrosis hepática en ausencia de enfermedad cardíaca preexistente. Su prevalencia es variable de acuerdo a lo reportado por diferentes grupos de investigación debido a que puede mantenerse subclínica o latente hasta que la pone de manifiesto una situación de estrés como una cirugía, hemorragia, infección, trasplante hepático o shunt porto-sistémico intrahepático transyugular. El objetivo de esta revisión es discutir la definición, los fundamentos anátomo-patológicos, fisiopatología, manifestaciones clínicas, criterios de diagnóstico, importancia de los estudios con imágenes, relevancia clínica, tratamiento farmacológico y trasplante hepático.

Autoimmune hepatitis recurrence after liver transplantation: "Les jeux sont faits".

Autoimmune hepatitis (AIH) may recur after liver transplantation (LT). The aims of this study were to evaluate the incidence and risk factors for recurrent autoimmune hepatitis (rAIH). A multicenter retrospective French nationwide study, including all patients aged ≥16 transplanted for AIH, with at least 1 liver biopsy 1 year after LT, was conducted between 1985 and 2018. Risk factors for rAIH were identified using a multivariate Cox regression model. Three hundred and forty-four patients were included (78.8% women) with a median age at LT of 43.6 years. Seventy-six patients (22.1%) developed recurrence in a median time of 53.6 months (IQR, 14.1-93.2). Actuarial risk for developing rAIH was 41.3% 20 years after LT. In multivariate analysis, the strongest risk factor for rAIH was cytomegalovirus D+/R- mismatch status (HR=2.0; 95% CI: 1.1-3.6; p =0.03), followed by associated autoimmune condition. Twenty-one patients (27.6% of rAIH patients) developed liver graft cirrhosis after rAIH. Independent risk factors for these severe forms of rAIH were young age at LT, IgG levels >20.7 g/L, and LT in the context of (sub)fulminant hepatitis. Immunosuppression, especially long-term maintenance of corticosteroid therapy, was not significantly associated with rAIH. Recurrence of AIH after LT is frequent and may lead to graft loss. Recurrence is more frequent in young patients with active disease at the time of LT, yet systematic corticosteroid therapy does not prevent it.

Long-term outcome of liver transplantation for autoimmune hepatitis: A French nationwide study over 30 years.

BACKGROUND & AIMS: Autoimmune hepatitis (AIH) is a rare indication for liver transplantation (LT). The aims of this study were to evaluate long-term survival after LT for AIH and prognostic factors, especially the impact of recurrent AIH (rAIH). METHODS: A multicentre retrospective nationwide study including all patients aged ≥16 transplanted for AIH in France was conducted. Early deaths and retransplantations (≤6 months) were excluded. RESULTS: The study population consisted of 301 patients transplanted from 1987 to 2018. Median age at LT was 43 years (IQR, 29.4-53.8). Median follow-up was 87.0 months (IQR, 43.5-168.0). Seventy-four patients (24.6%) developed rAIH. Graft survival was 91%, 79%, 65% at 1, 10 and 20 years respectively. Patient survival was 94%, 84% and 74% at 1, 10 and 20 years respectively. From multivariate Cox regression, factors significantly associated with poorer patient survival were patient age ≥58 years (HR = 2.9; 95% CI, 1.4-6.2; p = 0.005) and occurrence of an infectious episode within the first year after LT (HR = 2.5; 95% CI, 1.2-5.1; p = 0.018). Risk factors for impaired graft survival were: occurrence of rAIH (HR = 2.7; 95% CI, 1.5-5.0; p = 0.001), chronic rejection (HR = 2.9; 95% CI, 1.4-6.1; p = 0.005), biliary (HR = 2.0; 95% CI, 1.2-3.4; p = 0.009), vascular (HR = 1.8; 95% CI, 1.0-3.1; p = 0.044) and early septic (HR = 2.1; 95% CI, 1.2-3.5; p = 0.006) complications. CONCLUSION: Our results confirm that survival after LT for AIH is excellent. Disease recurrence and chronic rejection reduce graft survival. The occurrence of an infectious complication during the first year post-LT identifies at-risk patients for graft loss and death.

Review article: diagnosis, pathophysiology and management of atrial fibrillation in cirrhosis and portal hypertension.

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia and its management in cirrhosis can be challenging due to the altered hepatic metabolism of medications and increased risk of bleeding. AIMS: To provide a comprehensive overview of the diagnosis, pathophysiology and management of AF in patients with cirrhosis from both a cardiology and a hepatology perspective. METHODS: An extensive literature search was performed using the terms 'atrial fibrillation' and 'cirrhosis'. Guideline documents and consensus statements were explored. RESULTS: The prevalence of AF in patients with cirrhosis ranges between 6.6% and 14.2%, while the incidence of new-onset AF in the post-operative period after liver transplant ranged between 6.8% and 10.2%. AF in patients with cirrhosis is associated with adverse outcomes in both pre-transplant and post-transplant settings, including an increased risk of stroke when compared to the general population. We review the pathogenesis of AF in general and in cirrhosis. This review also provides guidance on the management of AF, including the use of anticoagulation and rate versus rhythm control. In the absence of strict contraindications, all patients with cirrhosis and AF should be anticoagulated. The use of DOACs is preferred over vitamin K antagonists. In patients with a high bleeding risk, a DOAC with an approved antidote may be preferred. CONCLUSIONS: Atrial fibrillation is increased in patients with cirrhosis. AF management requires careful consideration of treatment options. Since patients with cirrhosis were excluded from all major randomised clinical trials, dedicated research on the pathophysiology and management of AF in cirrhosis is needed.

Liver transplantation for autoimmune hepatitis: Pre-transplant does not predict the early post-transplant outcome.

BACKGROUND AND AIMS: Autoimmune hepatitis (AIH) is a rare indication (<5%) for liver transplantation (LT). The aim of this study was to describe the early outcome after LT for AIH. METHODS: A multicenter retrospective nationwide study including all patients aged ≥16 transplanted for AIH in France was conducted. Occurrences of biliary and vascular complications, rejection, sepsis, retransplantation and death were collected during the first year after LT. RESULTS: A total of 344 patients (78.8% of women, 17.0% of (sub)fulminant hepatitis and 19.2% of chronic liver diseases transplanted in the context of acute-on-chronic liver failure [ACLF]) were included, with a median age at LT of 43.6 years. Acute rejection, sepsis, biliary and vascular complications occurred in respectively 23.5%, 44.2%, 25.3% and 17.4% of patients during the first year after LT. One-year graft and patient survivals were 84.3% and 88.0% respectively. The main cause of early death was sepsis. Pre-LT immunosuppression was not associated with an increased risk for early infections or surgical complications. Significant risk factors for septic events were LT in the context of (sub)fulminant hepatitis or ACLF, acute kidney injury at the time of LT (AKI) and occurrence of biliary complications after LT. AKI was the only independent factor associated with graft (HR = 2.5; 95% CI: 1.1-5.4; p = .02) and patient survivals (HR = 2.6; 95% CI: 1.0-6.5; p = .04). CONCLUSION: Early prognosis is good after LT for AIH and is not impacted by pre-LT immunosuppression but by the presence of AKI at the time of LT.

Cardiovascular events after liver transplantation: MACE hurts.

The curative therapy for patients with end-stage liver disease is liver transplantation. However, liver transplantation challenges the cardiovascular system, and is associated with major adverse cardiovascular events (MACE). Immediately after implantation of the liver graft, changes in cardiac preload and afterload increase the cardiac workload. Longer-term postoperatively, a more sedentary lifestyle and enhanced appetite increase obesity and body mass index. Immunosuppressants may also affect the cardiovascular system. All these factors that liver recipients encounter impact the function of the cardiovascular system. Cardiac events are the third-leading cause of death in liver recipients. This review describes the pertinent factors that predispose to development of MACE after liver transplantation, and how to predict these cardiovascular events in the post-transplant period. We review the roles of metabolic syndrome, renal dysfunction, non-alcoholic fatty liver disease, diagnostic tests such as imaging and biomarkers, and parameters such as systolic and diastolic dysfunction, and QT interval prolongation in cardiovascular events. We summarize the current literature on scoring systems to predict cardiovascular events.

Risk factors of de novo malignancies after liver transplantation: a French national study on 11004 adult patients.

BACKGROUND: After liver transplantation (LT),de novo malignancies are one of the leading causes of late mortality. The aim of the present retrospective study was to identify the risk factors of de novo malignancies in a large cohort of LT recipients in France, using Fine and Gray competing risks regression analysis. METHODS: The study population consisted in 11004 adults transplanted between 2000 and 2013, who had no history of pre-transplant malignancy, except primary liver tumor. A Cox model adapted to the identification of prognostic factors (competitive risks) was used. RESULTS: From the entire cohort, one (or more)de novo malignancy was reported in 1480 L T recipients (13.45%). The probability to develop a de novo malignancy after LT was 2.07% at 1 year, 13.30% at 5 years, and 28.01% at 10 years. Of the known reported malignancies, the most common malignancies were hematological malignancy (22.36%), non-melanoma skin cancer (19.53%) and lung cancer (12.36%). According to Fine and Gray competing risks regression multivariate analysis, were significant risk factors for post-LT de novo malignancy: recipient age (Subdistribution Hazard Ratio (SHR) = 1.03 95%CI 1.03-1.04), male gender (SHR = 1.45 95%CI 1.27-1.67), non-living donor (SHR = 1.67 95%CI 1.14-2.38), a first LT (SHR = 1.35 95%CI 1.09-1.69) and the type of initial liver disease (alcohol-related liver disease (SHR = 1.63 95%CI 1.22-2.17), primary sclerosing cholangitis (SHR = 1.98 95%CI 1.34-2.91), and primary liver tumor (SHR = 1.88 95%CI 1.41-2.54)). Initial immunosuppressive regimen had no significant impact. CONCLUSION: The present study confirms that LT recipient characteristics are associated with the risk ofde novo malignancy and this underlines the need for personalized screening in order to improve survival.

Covid-19 in liver transplant recipients: the French SOT COVID registry.

BACKGROUND: Notwithstanding the ongoing coronavirus disease-2019 (Covid-19) pandemic, information on its clinical presentation and prognosis in organ transplant recipients remains limited. The aim of this registry-based observational study was to report the characteristics and clinical outcomes of liver transplant (LT) recipients included in the French nationwide Registry of Solid Organ Transplant Recipients with Covid-19. METHODS: COVID-19 was diagnosed in patients who had a positive PCR assay for SARS-CoV-2 or in presence of typical lung lesions on imaging or specific SARS-CoV-2 antibodies. Clinical and laboratory characteristics, management of immunosuppression, treatment for Covid-19, and clinical outcomes (hospitalization, admission to intensive care unit, mechanical ventilation, or death) were recorded. RESULTS: Of the 104 patients, 67 were admitted to hospital and 37 were managed at home (including all 13 children). Hospitalized patients had a median age of 65.2 years (IQR: 58.1 - 73.2 years) and two thirds were men. Most common comorbidities included overweight (67.3%), hypertension (61.2%), diabetes (50.7%), cardiovascular disease (20.9%) and respiratory disease (16.4%). SARS-CoV-2 infection was identified after a median of 92.8 months (IQR: 40.1 - 194.7 months) from LT. During hospitalization, antimetabolites, mTOR inhibitor, and CNIs were withdrawn in 41.9%, 30.0% and 12.5% of patients, respectively. The composite endpoint of severe Covid-19 within 30 days after diagnosis was reached by 33.0% of the adult patients. The 30-day mortality rate was 20.0%, and 28.1% for hospitalized patients. Multivariate analysis identified that age was independently associated with mortality. CONCLUSION: In our large nationwide study, Covid-19 in LT recipients was associated with a high mortality rate.

Over-diagnosed prostate cancer in solid organ recipients: lessons from the last 3 decades.

INTRODUCTION: Prostate cancer (PC) is the most common neoplasia in men. With aging of solid organ transplant recipients (SOTR), its incidence is likely to increase. The aim of this study was to analyze PC screening results retrospectively in renal transplant recipients (RTR), hepatic transplant recipients (HTR) and cardiac transplant recipients (CTR). PATIENTS AND METHODS: A retrospective monocentric study of PC diagnosed in renal, hepatic or cardiac transplanted patients since 1989 was performed. All the patients were followed annually by digital rectal examination and prostate serum antigen (PSA) dosage. RESULTS: 57 PC were diagnosed in 1565 SOTR male patients (3.6%): 35 RTR, 15 HTR, and 7 CTR. Standard incidence ratio (SIR) was 41.9. Mean age at the time of diagnosis was 64.5 (60.5-69.2). Mean time between transplantation and PC diagnosis was 95.7 (39.0-139.5) months. Median PSA rate was 7.0 (6.2-13) ng/mL. Clinical stages were T1, T2, and T3, respectively, for 29, 22 and 6 patients. Diagnosis was done by screening in 52 patients, after prostatitis in 1 and bone pain in another. Three PC were discovered on prostate chips after transurethral resection. Two patients were treated by active surveillance. 39 (68%) patients (25 RTR, 11 HTR and 3 CTR) were treated by radical prostatectomy. Histological results were 30 pT2 and 9 pT3 tumors, with 7 positive surgical margins. Gleason score was 5, 6, 7, 8 and 9 in, respectively, in 2, 24, 11, 1 and 1 patients. One patient with positive pelvic nodes was treated with hormonal therapy (HT). One had a biochemical relapse at 10 months and underwent salvage radiotherapy. Median follow-up was 85.2 months (46.1-115.0). 23 (40.4%) patients died. Two (3.6%) RTR and 1 (1.8%) CTR died from their PC. Standard incidence ratio were, respectively, 42.4, 48.2 and 39 in RTR, HTR and CTR. CONCLUSION: Systematic screening in male SOTR after 50 years old could not be recommended. In the last 3 decades, we diagnosed too many low-risk prostate cancers strongly increasing the SIR but failing to decrease prostate cancer related mortality. SOTR should undergo individual screening with prior MRI when PSA rates are high. Management should not be different from that of the general population.

Redefining Cirrhotic Cardiomyopathy for the Modern Era.

Cirrhotic cardiomyopathy (CCM) is cardiac dysfunction in patients with end-stage liver disease in the absence of prior heart disease. First defined in 2005 during the World Congress of Gastroenterology, CCM criteria consisted of echocardiographic parameters to identify subclinical cardiac dysfunction in the absence of overt structural abnormalities. Significant advancements in cardiovascular imaging over the past 14 years, including the integration of myocardial deformation imaging into routine clinical practice to identify subclinical cardiovascular dysfunction, have rendered the 2005 CCM criteria obsolete. Therefore, new criteria based on contemporary cardiovascular imaging parameters are needed. In this guidance document, assembled by a group of multidisciplinary experts in the field, new core criteria based on contemporary cardiovascular imaging parameters are proposed for the assessment of CCM. This document provides a critical assessment of the diagnosis of CCM and ongoing assessment aimed at improving clinical outcomes, particularly surrounding liver transplantation. Key points and practice-based recommendations for the diagnosis of CCM are provided to offer guidance for clinicians and identify gaps in knowledge for future investigations.

Understanding and managing cardiovascular outcomes in liver transplant recipients.

PURPOSE OF REVIEW: Cardiovascular disease (CVD) is a common cause of mortality after liver transplantation. The transplant community is focused on improving long-term survival. Understanding the prevalence of CVD in liver transplant recipients, precipitating factors as well as prevention and management strategies is essential to achieving this goal. RECENT FINDINGS: CVD is the leading cause of death within the first year after transplant. Arrhythmia and heart failure are the most often cardiovascular morbidities in the first year after transplant which could be related to pretransplant diastolic dysfunction. Pretransplant diastolic dysfunction is reflective of presence of cirrhotic cardiomyopathy which is not as harmless as it was thought. Multiple cardiovascular risk prediction models have become available to aid management in liver transplant recipients. SUMMARY: A comprehensive prevention and treatment strategy is critical to minimize cardiovascular morbidity and mortality after liver transplant. Weight management and metabolic syndrome control are cornerstones to any prevention and management strategy. Bariatric surgery is an underutilized tool in liver transplant recipients. Awareness of 'metabolic-friendly' immunosuppressive regimens should be sought. Strict adherence to the cardiology and endocrine society guidelines with regard to managing metabolic derangements post liver transplantation is instrumental for CVD prevention until transplant specific recommendations can be made.

Longterm Risk of Solid Organ De Novo Malignancies After Liver Transplantation: A French National Study on 11,226 Patients.

De novo malignancies are one of the major late complications and causes of death after liver transplantation (LT). Using extensive data from the French national Agence de la Biomédecine database, the present study aimed to quantify the risk of solid organ de novo malignancies (excluding nonmelanoma skin cancers) after LT. The incidence of de novo malignancies among all LT patients between 1993 and 2012 was compared with that of the French population, standardized on age, sex, and calendar period (standardized incidence ratio; SIR). Among the 11,226 LT patients included in the study, 1200 de novo malignancies were diagnosed (10.7%). The risk of death was approximately 2 times higher in patients with de novo malignancy (48.8% versus 24.3%). The SIR for all de novo solid organ malignancies was 2.20 (95% confidence interval [CI], 2.08-2.33). The risk was higher in men (SIR = 2.23; 95% CI, 2.09-2.38) and in patients transplanted for alcoholic liver disease (ALD; SIR = 2.89; 95% CI, 2.68-3.11). The cancers with the highest excess risk were laryngeal (SIR = 7.57; 95% CI, 5.97-9.48), esophageal (SIR = 4.76; 95% CI, 3.56-6.24), lung (SIR = 2.56; 95% CI, 2.21-2.95), and lip-mouth-pharynx (SIR = 2.20; 95% CI, 1.72-2.77). In conclusion, LT recipients have an increased risk of de novo solid organ malignancies, and this is strongly related to ALD as a primary indication for LT.

Recipient Selection for Optimal Utilization of Discarded Grafts in Liver Transplantation.

BACKGROUND: In France, liver grafts that have been refused by at least 5 teams are considered for rescue allocation (RA), with the choice of the recipient being at the team's discretion. Although this system permits the use of otherwise discarded grafts in a context of organ shortage, outcomes and potential benefits need to be assessed. METHODS: Between 2011 and 2015, outcomes of RA grafts (n = 33) were compared with SA grafts (n = 321) at a single French center. RESULTS: Liver grafts in the RA group were older (63 ± 17 years vs 54 ± 18 years, P = 0.007) and had a higher DRI (1.86 ± 0.45 vs 1.61 ± 0.47, P = 0.010). Recipients in this group had a lower Model for End-Stage Liver Disease score (14 ± 5 vs 22 ± 10, P < 0.001) and had mostly hepatocellular carcinoma (67.0% vs 40.4%, P = 0.010). The balance of risk score was significantly lower in the RA group (5.5 ± 2.9 vs 9.2 ± 5.5, P < 0.001). There were higher rates of early and delayed hepatic artery thrombosis (15.2% vs 3.1%, P = 0.001) and retransplantation (18.2% vs 4.7%, P = 0.002) in the RA group. Patient survival was not different between groups, but graft survival was impaired (95% vs 82% at 1 year and 94% vs 74% at 3 years, P = 0.001). CONCLUSION: Our results show that discarded liver grafts can be used provided that there is a strict recipient selection process, although hepatic artery thrombosis and retransplantation are more frequent. This strategy enables utilization of otherwise discarded grafts in the context of organ shortage.

Conversion From Once-Daily Prolonged-Release Tacrolimus to Once-Daily Extended-Release Tacrolimus in Stable Liver Transplant Recipients.

OBJECTIVES: After organ transplant, strategies to simplify the therapeutic regimen may improve adherence and prevent rejection and/or graft loss. The aim of the present study was to evaluate the safety of conversion from once-daily prolonged-release tacrolimus (Advagraf; Astellas Pharma Europe Limited, Middlesex, UK) to once-daily extended-release tacrolimus (Envarsus; Chiesi SAS, Nanterre, France) in stable adult liver transplant recipients. MATERIALS AND METHODS: This observational study inclu-ded 44 liver transplant patients (median age of 59 y; 63.6% men; median delay after transplant of 72.5 mo). Conversion was based on a 1:0.70 proportion. RESULTS: Mean dose of tacrolimus was 2.65 ± 1.24 mg/day before conversion and 2.09 ± 1.68 mg/day after conversion (P < .05), with ratio of 1:0.79. Mean serum tacrolimus trough level increased after conversion (4.92 ± 1.65 vs 5.60 ± 2.89 ng/mL; P < .05), with ratio of 1:1.14. Six months after conversion, mean dose of tacrolimus was 1.65 ± 0.93 mg/day (ratio of 1:0.62) and mean serum tacrolimus trough level was 4.82 ± 1.85 ng/mL, similar to the initial level before conversion. At the end of follow-up, 2 patients had returned to once-daily prolonged-release tacrolimus because of adverse effects (allergy, digestive trouble), which resolved thereafter. The mean cost of tacrolimus therapy was 5.54 ± 2.29 Euros/patient/day before conversion and 4.11 ± 2.32 Euros/patient/day after conversion (P < .05). CONCLUSIONS: Conversion from prolonged-release to extended-release tacrolimus in stable liver transplant patients is safe and cost-effective; however, initially, dose adaptations and careful monitoring are required.

Ripening Transcriptomic Program in Red and White Grapevine Varieties Correlates with Berry Skin Anthocyanin Accumulation.

Grapevine (Vitis vinifera) berry development involves a succession of physiological and biochemical changes reflecting the transcriptional modulation of thousands of genes. Although recent studies have investigated the dynamic transcriptome during berry development, most have focused on a single grapevine variety, so there is a lack of comparative data representing different cultivars. Here, we report, to our knowledge, the first genome-wide transcriptional analysis of 120 RNA samples corresponding to 10 Italian grapevine varieties collected at four growth stages. The 10 varieties, representing five red-skinned and five white-skinned berries, were all cultivated in the same experimental vineyard to reduce environmental variability. The comparison of transcriptional changes during berry formation and ripening allowed us to determine the transcriptomic traits common to all varieties, thus defining the core transcriptome of berry development, as well as the transcriptional dynamics underlying differences between red and white berry varieties. A greater variation among the red cultivars than between red and white cultivars at the transcriptome level was revealed, suggesting that anthocyanin accumulation during berry maturation has a direct impact on the transcriptomic regulation of multiple biological processes. The expression of genes related to phenylpropanoid/flavonoid biosynthesis clearly distinguished the behavior of red and white berry genotypes during ripening but also reflected the differential accumulation of anthocyanins in the red berries, indicating some form of cross talk between the activation of stilbene biosynthesis and the accumulation of anthocyanins in ripening berries.