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Rosellina Margherita Mancina,1,* Flaminia Ferri,2,* Alessio Farcomeni,3 Antonio Molinaro,1 Angela Maffongelli,4 Monica Mischitelli,2 Edoardo Poli,2 Lucia Parlati,5 Maria Antonella Burza,6 Adriano De Santis,2 Fabio Attilia,2 Claudia Rotondo,2 Maria Margherita Rando,2 Maria Luisa Attilia,2 Mauro Ceccanti,2 Stefano Ginanni Corradini2 1Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at the University of Gothenburg, Wallenberg Laboratory, Göteborg, Sweden; 2Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy; 3Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy; 4Department of General Surgery, Urgency and Organ Transplantation, University Hospital “Paolo Giaccone”, University of Palermo, Palermo, Italy; 5Hepatology Department, Université Paris Descartes, Cochin Hospital, APHP, Paris, France; 6Department of Medicine, Division of Gastroenterology and Hepatology, Sahlgrenska University Hospital, Gothenburg, Sweden *These authors contributed equally to this work Background: Alcoholic cirrhosis represents 1% of all cause-of-deaths worldwide. Its incidence is higher in males and results from the combination of environmental and genetic factors. Among all the genetic determinants of alcoholic cirrhosis, the patatin-like phospholipase domain protein 3 (PNPLA3) rs738409 represents the most widely validated determinant. Recent cross-sectional studies on alcohol abusers identified transmembrane-6 superfamily member 2 (TM6SF2) rs58542926, membrane bound O-acyltransferase domain containing 7 (MBOAT7) rs641738, and cluster of differentiation 14 (CD14) rs2569190 as new genetic risk factors for alcoholic cirrhosis. We aimed to develop a gene-based risk score to predict the incidence of alcoholic cirrhosis in males with at-risk alcohol consumption.Materials and methods: A total of 416 male at-risk alcohol drinkers were retrospectively examined. The association between alcoholic cirrhosis incidence and PNPLA3, CD14, TM6SF2, and MBOAT7 variants was tested. Age at onset of at-risk alcohol consumption, age, and body mass index (BMI) were included as covariates to determine the prediction score for alcoholic cirrhosis incidence by evaluating time-dependent receiver operating characteristic curves.Results: We found that PNPLA3, CD14, and TM6SF2 were associated with alcoholic cirrhosis prevalence. PNPLA3 and CD14 were also associated with its incidence. The best predictive score formula was (age at onset of at-risk alcohol consumption × 0.1) + (number of CD14 allele T) + (number of PNPLA3 allele M) + (BMI × 0.1). A threshold of 7.27 was identified as cutoff for the predictive risk of alcoholic cirrhosis development in 36 years from the onset of at-risk alcohol consumption with 70.1% sensitivity and 78.7% specificity.Conclusion: We developed the first score for alcoholic cirrhosis prediction that combines clinical and genetic factors. Keywords: alcoholic cirrhosis, PNPLA3, CD14, predictive score

Focuses on the prevalence of infection with polyomaviruses JC and BK. Indication of respiratory symptoms during primary childhood infections by BK virus; Association of reactivated infections to cases of haemorrhagic cystitis and ureteric stenosis; Potential of BK virus for transformation of cell cultures from various species.

Focuses on the human polyomavirus JC virus considered as the etiological agent of progressive multifocial leukoencephalopathy associated with immunodepression and frequent in AIDS patients. Evidence of genetic variability in the non-coding control region in virus; Characterization of viral variants; Assessment on the presence of JC virus genome in different biological samples.

Focuses on the association of haemorrhagic cystitis related to BK virus infection after stem cell transplantation particularly allogenic bone marrow transplant. Role of BK virus reactivation with the complication; Diagnosis of haemorrhagic cystitis; Evaluation on the incidence ad the aetiology of haemorrhagic cystitis.

Abstract Background Nowadays, better immunosuppressors have decreased the rates of acute rejection in kidney transplantation, but have also led to the emergence of BKV-associated nephropathy (BKVAN). Therefore, we prospectively investigated BKV load in plasma and urine samples in a cohort of kidney transplants, receiving basiliximab combined with a mycophenolate mofetil-based triple immunotherapy, to evaluate the difference between BKV replication during the first 3 months post-transplantation, characterized by the non-depleting action of basiliximab, versus the second 3 months, in which the maintenance therapy acts alone. We also performed sequencing analysis to assess whether a particular BKV subtype/subgroup or transcriptional control region (TCR) variants were present. Methods We monitored BK viruria and viremia by quantitative polymerase chain reaction (Q-PCR) at 12 hours (Tx), 1 (T1), 3 (T2) and 6 (T3) months post-transplantation among 60 kidney transplant patients. Sequencing analysis was performed by nested-PCR with specific primers for TCR and VP1 regions. Data were statistically analyzed using χ2 test and Student's t-test. Results BKV was detected at Tx in 4/60 urine and in 16/60 plasma, with median viral loads of 3,70 log GEq/mL and 3,79 log GEq/mL, respectively, followed by a significant increase of both BKV-positive transplants (32/60) and median values of viruria (5,78 log GEq/mL) and viremia (4,52 log GEq/mL) at T2. Conversely, a significantly decrease of patients with viruria and viremia (17/60) was observed at T3, together with a reduction of the median urinary and plasma viral loads (4,09 log GEq/mL and 4,00 log GEq/mL, respectively). BKV TCR sequence analysis always showed the presence of archetypal sequences, with a few single-nucleotide substitutions and one nucleotide insertion that, interestingly, were all representative of the particular subtypes/subgroups we identified by VP1 sequencing analysis: I/b-2 and IV/c-2. Conclusions Our results confirm previous studies indicating that BKV replication may occur during the early hours after kidney transplantation, reaches the highest incidence in the third post-transplantation month and then decreases within the sixth month, maybe due to induction therapy. Moreover, it might become clinically useful whether specific BKV subtypes or rearrangements could be linked to a particular disease state in order to detect them before BKVAN onset.

Abstract Herpes simplex virus (HSV) infection is one of the most common viral sexually transmitted diseases worldwide. The first time infection of the mother may lead to severe illness in pregnancy and may be associated with virus transmission from mother to foetus/newborn. Since the incidence of this sexually transmitted infection continues to rise and because the greatest incidence of herpes simplex virus infections occur in women of reproductive age, the risk of maternal transmission of the virus to the foetus or neonate has become a major health concern. On these purposes the Authors of this review looked for the medical literature and pertinent publications to define the status of art regarding the epidemiology, the diagnosis, the therapy and the prevention of HSV in pregnant women and neonate. Special emphasis is placed upon the importance of genital herpes simplex virus infection in pregnancy and on the its prevention to avoid neonatal HSV infections.

Abstract Clinical diagnosis of kidney transplants related illnesses is not a simple task. Several studies were conducted to define diseases and complications after renal transplantation, but there are no comprehensive guidelines about diagnostic tools for their prevention and detection. The Authors of this review looked for the medical literature and pertinent publications in particular to understand the role of Human Polyomavirus BK (BKV) in renal failure and to recognize analytical techniques for BK virus associated nephropathy (BKVAN) detection.

In cirrhotic patients listed for liver transplantation (LT) with a history of hepatic encephalopathy (HE), rifaximin reduces the number of hospitalizations, but whether it influences the time to first hospitalization is unknown., Aims: to evaluate the time-dependent impact of rifaximin on the risk of all-cause hospitalization and dropout in patients on the LT waiting list., Methods: Consecutive patients listed for LT were retrospectively enrolled. After balancing populations with and without rifaximin treatment using the inverse probability therapy weighting analysis, Fine-Gray multivariable competing risk analyses were run to explore risk factors for the first episode of hospitalization and dropout., Results: When comparing 92 patients taking rifaximin to the untreated group of 152, rifaximin treatment was not associated with any of the study outcomes. In the subset of patients with a history of HE at waitlist entry (N = 81 rifaximin-treated and N = 39 untreated), rifaximin intake was independently associated with a lower risk of hospitalization for all causes (SHR 0.638; 95.0% CI 0.418-0.973; p = 0.037) and for HE (SHR 0.379; 95.0% CI 0.207-0.693; p = 0.002)., Conclusions: cirrhotic LT candidates with a prior history of HE rifaximin treatment are associated with a lower risk of time-dependent all-cause hospitalization, likely due to its unique effect on gut microbiome composition/function.

Liver cirrhosis development is a multifactorial process resulting from a combination of environmental and genetic factors. The aim of the study was to develop accurate non-invasive diagnostic and prognostic models for alcoholic cirrhosis. Consecutive subjects with at-risk alcohol intake were retrospectively enrolled (110 cirrhotic patients and 411 non-cirrhotics). At enrollment, the data about lifetime drinking history were collected and all patients were tested for Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409, Transmembrane 6 Superfamily 2 (TM6SF2) rs58542926, and hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) rs72613567 variants. In cross-sectional analyses, models for the diagnosis of cirrhosis were developed using multivariate logistic regression. A predictive score for cirrhosis development over 24 years was built by evaluating time-dependent AUC curves. The best diagnostic accuracy was demonstrated by the model, which also includes daily alcohol consumption, duration of hazardous alcohol use, and genetic variants, with AUCs of 0.951 (95% CI 0.925-0.977) and 0.887 (95% CI 0.925-0.977) for cirrhosis and compensated cirrhosis, respectively. The predictive model for future cirrhosis development (AUC of 0.836 95% CI: 0.769-0.904) accounted for age at onset of at-risk alcohol consumption and the number of PNPLA3 and HSD17B13 variant alleles. We have developed accurate genetic and alcohol consumption models for the diagnosis of alcoholic cirrhosis and the prediction of its future risk.

We aimed to evaluate the magnesium content in human cirrhotic liver and its correlation with serum AST levels, expression of hepatocellular injury, and MELDNa prognostic score. In liver biopsies obtained at liver transplantation, we measured the magnesium content in liver tissue in 27 cirrhotic patients (CIRs) and 16 deceased donors with healthy liver (CTRLs) by atomic absorption spectrometry and within hepatocytes of 15 CIRs using synchrotron-based X-ray fluorescence microscopy. In 31 CIRs and 10 CTRLs, we evaluated the immunohistochemical expression in hepatocytes of the transient receptor potential melastatin 7 (TRPM7), a magnesium influx chanzyme also involved in inflammation. CIRs showed a lower hepatic magnesium content (117.2 (IQR 110.5-132.9) vs. 162.8 (IQR 155.9-169.8) μg/g; p < 0.001) and a higher percentage of TRPM7 positive hepatocytes (53.0 (IQR 36.8-62.0) vs. 20.7 (10.7-32.8)%; p < 0.001) than CTRLs. In CIRs, MELDNa and serum AST at transplant correlated: (a) inversely with the magnesium content both in liver tissue and hepatocytes; and (b) directly with the percentage of hepatocytes stained intensely for TRPM7. The latter also directly correlated with the worsening of MELDNa at transplant compared to waitlisting. Magnesium depletion and overexpression of its influx chanzyme TRPM7 in hepatocytes are associated with severity of hepatocyte injury and prognosis in cirrhosis. These data represent the pathophysiological basis for a possible beneficial effect of magnesium supplementation in cirrhotic patients.

(1) Background: We investigated, for the first time, whether dietary simple sugar intake affects MELD score changes over time in a cohort of cirrhotic liver transplant candidates. (2) Methods: the MELD score, dietary habits using a 3-day food diary, and visceral adipose tissue index (VATI) measured with CT scan were assessed in 80 consecutive outpatient cirrhotic patients at baseline, after counseling to follow current nutritional guidelines. The MELD score was reassessed after six months and the DELTA-MELD was calculated as the MELD at the second assessment minus the MELD at baseline. (3) Results: Compared with the baseline, the MELD score of cirrhotic patients at the end of the study was decreased, stable, or increased in 36%, 8% and 56% of patients, respectively. In separate multiple linear regression models, DELTA-MELD was positively and independently correlated with the daily intake of simple sugars expressed in g/kg body weight ( p = 0.01) or as a percentage of total caloric intake ( p = 0.0004) and with the number of daily portions of fruit, added sugar, jam, and honey ( p = 0.003). These associations were present almost exclusively in patients with VATI above the median value. (4) Conclusions: In cirrhotic patients with high amounts of visceral adipose tissue the consumption of simple sugars and fructose should be limited to improve their clinical outcome.