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Transjugular intrahepatic portosystemic shunt (TIPS) has been demonstrated to be feasible in older adult patients (age ≥70 years), yet the selection criteria remain suboptimal. Sarcopenia, highly prevalent in elderly population, may be significantly associated with post-TIPS outcome. This study aimed at evaluating the impact of baseline sarcopenia on post-TIPS survival in older adults with cirrhosis. A retrospective analysis of the prospective Italian TIPS-Registry was conducted to identify patients ≥70 years who received TIPS from June 2015 to March 2023. The availability of baseline abdominal CT scan was a mandatory inclusion criterion. Skeletal muscle index (SMI) was evaluated at the L3-L4 level. Sarcopenia was defined as SMI <50 cm2/m2 for men and <39 cm2/m2 for women. Probability of liver-related death was evaluated by competing risks analysis. A prediction model for liver-related mortality was created. One-hundred and fifteen patients were included: median age 74 years (IQR 3.1), 62% male, median dry-BMI 25.7 (IQR 4.7), 60% prevalence of sarcopenia. The main etiologies were viral (40%), alcohol-associated cirrhosis (23%), and metabolic dysfunction-associated steatohepatitis (20%). Refractory ascites (57%) was the main indications for TIPS. During a mean follow up of 20 months (IQR 20), 40 (34.8%) patients died for liver-related causes and 16 (13.9%) for extrahepatic causes. Liver-related mortality was significantly higher in patients with sarcopenia than in those without (6-months: 25.0% vs. 2.2%; 1-year: 43.0% vs. 4.8%, respectively; p value <0.001). A predictive model including INR, creatinine, and sarcopenia was developed to estimate liver-related mortality. The model achieved good predictive performances with AUCs of 0.826, 0.788, and 0.712 at 6-month, 1-year, and 2-years, respectively. Due to its significant impact on survival, the evaluation of sarcopenia may improve the selection of older adults candidate to TIPS. The new predictive model for post-TIPS liver-related mortality deserves external validation. [ABSTRACT FROM AUTHOR]

Transjugular intrahepatic portosystemic shunt (TIPS) is a well-established treatment for refractory ascites (RA) in patients with cirrhosis. However, a major drawback is the development of post-procedural hepatic encephalopathy (HE), which results from the diversion of blood from the portal vein. According to the first-pass effect, this diversion reduces the liver's capacity to metabolize substances from the gut, leading to an accumulation of toxic compounds in the brain. Given that liver perfusion relies on arterial compensation (hepatic arterial buffer), it is plausible that effective compensation, which also depends on cardiac function, may reduce the risk of encephalopathy by detoxifying the blood during the second-pass metabolism. To evaluate by Dynamic Contrast Enhanced-Magnetic Resonance Imaging (DCE-MRI) the changes in liver perfusion induced by TIPS in patients with RA and their relationship with the risk of HE. Twenty-nine consecutive patients underwent DCE-MRI, cardiac and hepatic hemodynamic evaluation before and after TIPS. MRI images were processed by a homemade software using the Dual Input Dual Compartment (DIDC) model, focusing on perfusion parameters. The DIDC model showed that total hepatic perfusion decreased by 24% after TIPS (248 ml/min/100ml vs 189 ml/min/100ml, p 0.095). As expected, a significant reduction in portal perfusion (decreased by 67%; 128.6 ml/min/100ml vs 42.4 ml/min/100ml, p 0.004) and an increase in hepatic arterial fraction post-TIPS (48% vs 77%, p 0.001) was observed. Post-TIPS residual total hepatic perfusion inversely correlated with one-year HE risk: patients with perfusion ≤ 130 ml/min/100ml had a HE risk of 67.6% vs 36.4% for those > 130 ml/min/100ml (HR: 2.1, p 0.039). Perfusion MRI is able to elucidate the impact of TIPS on liver perfusion, quantifying the extent of hepatic perfusion and its correlation with the development of post-TIPS HE. [ABSTRACT FROM AUTHOR]

Background/Objectives : We evaluated the relationship between the neoangiogenic transcriptomic signature (nTS) and clinical symptoms, treatment outcomes, and survival in hepatocellular carcinoma (HCC) patients. Methods : This study prospectively followed 328 patients in the derivation and 256 in the validation cohort (with a median follow-up of 31 and 22 months, respectively). The nTS was associated with disease presentation, treatments administered, and overall survival rates. Additionally, this study investigated how multiple treatments influenced changes in nTS status and alterations in microRNA expression. Results : The nTS was identified in 27.4% of patients, linked to aggressive features like multifocality and elevated alpha-fetoprotein (AFP), a pattern consistent with that of the validation cohort. Most patients in both cohorts received treatment for HCC. nTS+ patients had limited access to, and benefited less from, liver transplantation or radiofrequency ablation (RFA) compared to nTS- patients. By the end, 78.9% had died, with nTS- patients showing better median survival and response to treatments than their nTS+ counterparts, who had lower survival across all treatment types. Among those who received transarterial chemoembolization (TACE), 31.2% (21/80 patients after the initial treatment and another four following a second TACE) transitioned from an nTS- to an nTS+ status. This shift was associated with lower survival and alterations in microRNA expressions related to oncogenic pathways. Conclusions : The nTS markedly influences treatment eligibility and survival in patients with HCC. Notably, the nTS can develop after repeated TACE procedures, significantly impacting patient survival and altering oncogenic microRNA expression patterns. These findings highlight the critical role of the nTS in guiding treatment decisions and prognostication in HCC management.

Purpose: Warming up before competition is universally recognized as an effective way to enhance performance. However, only a few articles have directly investigated different warm-up strategies adopted by triathletes and suggested by coaches. The Olympic-distance triathlon is an endurance competition characterized, at least for the elite, by a fast start with a strong correlation to the final position in the race. Thus, executing a proper warm-up protocol would be beneficial in optimizing performance. The present study aimed to provide an overview of the warm-up protocol adopted/suggested by national-caliber triathletes/coaches before an Olympic-distance triathlon race., Methods: Online surveys were created and shared between national- and international-caliber Italian, French, and Spanish triathletes and coaches. Information about the rationale, structure, and specific exercises adopted/suggested during personal warm-up protocols was collected. Thereafter, triathletes were grouped according to the discipline sequence reported., Results: Seventy-nine triathletes and nineteen coaches completed the survey. The cycle-run-swim was the most reported discipline sequence adopted, with a total time of 90.0 (25.0) minutes, against the 62.5 (25.0) minutes suggested by coaches. Conditioning exercises were performed by only 31.6% of triathletes 20 to 10 minutes before the race start., Conclusions: Triathletes who took part in this survey adopted very long protocols with the specific intention of including all disciplines. These results highlight the need to raise awareness in triathletes and coaches on the correct warm-up procedures and to stimulate researchers to design studies that directly investigate the effects of different warm-up protocols before competitions.

Background & Aims: Overt hepatic encephalopathy (OHE) is a major complication of transjugular intrahepatic portosystemic shunt (TIPS) placement, given its high incidence and possibility of refractoriness to medical treatment. Nevertheless, the impact of post-TIPS OHE on mortality has not been investigated in a large population., Methods: We designed a multicenter, non-inferiority, observational study to evaluate the mortality rate at 30 months in patients with and without OHE after TIPS. We analyzed a database of 614 patients who underwent TIPS in three Italian centers and estimated the cumulative incidence of OHE and mortality with competitive risk analyses, setting the non-inferiority limit at 0.12., Results: During a median follow-up of 30 months (IQR 12-30), 293 patients developed at least one episode of OHE. Twenty-seven (9.2%) of them experienced recurrent/persistent OHE. Patients with OHE were older (64 [57-71] vs. 59 [50-67] years, p <0.001), had lower albumin (3.1 [2.8-3.5] vs. 3.25 [2.9-3.6] g/dl, p = 0.023), and had a higher prevalence of pre-TIPS OHE (15.4% vs. 9.0%, p = 0.023). Child-Pugh and MELD scores were similar. The 30-month difference in mortality between patients with and without post-TIPS OHE was 0.03 (95% CI -0.042 to 0.102). Multivariable analysis showed that age (subdistribution hazard ratio 1.04, 95% CI 1.02-1.05, p <0.001) and MELD score (subdistribution hazard ratio 1.09, 95% CI 1.05-1.13, p <0.001), but not post-TIPS OHE, were associated with a higher mortality rate. Similar results were obtained when patients undergoing TIPS for variceal re-bleeding prophylaxis (n = 356) or refractory ascites (n = 258) were analyzed separately. The proportion of patients with persistent OHE after TIPS was significantly higher in the group of patients who died. The robustness of these results was increased following propensity score matching., Conclusion: Episodic OHE after TIPS is not associated with mortality in patients undergoing TIPS, regardless of the indication., Impact and Implications: Overt hepatic encephalopathy (OHE) is a common complication in patients with advanced liver disease and it is particularly frequent following transjugular intrahepatic portosystemic shunt (TIPS) placement. In patients with cirrhosis outside the setting of TIPS, the development of OHE negatively impacts survival, regardless of the severity of cirrhosis or the presence of acute-on-chronic liver failure. In this multicenter, non-inferiority, observational study we demonstrated that post-TIPS OHE does not increase the risk of mortality in patients undergoing TIPS, irrespective of the indication. This finding alleviates concerns regarding the weight of this complication after TIPS. Intensive research to improve patient selection and risk stratification remains crucial to enhance the quality of life of patients and caregivers and to avoid undermining the positive effects of TIPS on survival., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Preterm infants cannot counteract excessive reactive oxygen species (ROS) production due to preterm birth, leading to an excess of lipid peroxidation with malondialdehyde (MDA) production, capable of contributing to brain damage. Melatonin (ME), an endogenous brain hormone, and its metabolites, act as a free radical scavenger against ROS. Unfortunately, preterms have an impaired antioxidant system, resulting in the inability to produce and release ME. This prospective, multicenter, parallel groups, randomized, double-blind, placebo-controlled trial aimed to assess: (i) the endogenous production of ME in very preterm infants (gestational age ≤ 29 + 6 WE, 28 infants in the ME and 26 in the placebo group); (ii) the exogenous hormone availability and its metabolization to the main metabolite, 6-OH-ME after 15 days of ME oral treatment; (iii) difference of MDA plasma concentration, as peroxidation marker, after treatment. Blood was collected before the first administration (T1) and after 15 days of administration (T2). ME and 6-OH-ME were detected by liquid chromatography tandem mass spectrometry, MDA was measured by liquid chromatograph with fluorescence detection. ME and 6-OH-ME were not detectable in the placebo group at any study time-point. ME was absent in the active group at T1. In contrast, after oral administration, ME and 6-OH-ME resulted highly detectable and the difference between concentrations T2 versus T1 was statistically significant, as well as the difference between treated and placebo groups at T2. MDA levels seemed stable during the 15 days of treatment in both groups. Nevertheless, a trend in the percentage of neonates with reduced MDA concentration at T2/T1 was 48.1% in the ME group versus 38.5% in the placebo group. We demonstrated that very preterm infants are not able to produce endogenous detectable plasma levels of ME during their first days of life. Still, following ME oral administration, appreciable amounts of ME and 6-OH-ME were available. The trend of MDA reduction in the active group requires further clinical trials to fix the dosage, the length of ME therapy and to identify more appropriate indexes to demonstrate, at biological and clinical levels, the antioxidant activity and consequent neuroprotectant potential of ME in very preterm newborns., (© 2023 The Authors. Journal of Pineal Research published by John Wiley & Sons Ltd.)

Portal hypertension (PH) constitutes a pivotal factor in the progression of cirrhosis, giving rise to severe complications and a diminished survival rate. The transjugular intrahepatic portosystemic shunt (TIPS) procedure has undergone significant evolution, with advancements in stent technology assuming a central role in managing PH-related complications. This review aims to outline the progression of TIPS and emphasizes the significant influence of stent advancement on its effectiveness. Initially, the use of bare metal stents (BMSs) was limited due to frequent dysfunction. However, the advent of expanding polytetrafluoroethylene-covered stent grafts (ePTFE-SGs) heralded a transformative era, greatly enhancing patency rates. Further innovation culminated in the creation of ePTFE-SGs with controlled expansion, enabling precise adjustment of TIPS diameters. Comparative analyses demonstrated the superiority of ePTFE-SGs over BMSs, resulting in improved patency, fewer complications, and higher survival rates. Additional technical findings highlight the importance of central stent placement and adequate stent length, as well as the use of smaller calibers to reduce the risk of shunt-related complications. However, improving TIPS through technical means alone is inadequate for optimizing patient outcomes. An extensive understanding of hemodynamic, cardiac, and systemic factors is required to predict outcomes and tailor a personalized approach. Looking forward, the ongoing progress in SG technology, paired with the control of clinical factors that can impact outcomes, holds the promise of reshaping the management of PH-related complications in cirrhosis.

Background and Aims: Implantation of a transjugular intrahepatic portosystemic shunt (TIPS) improves survival in patients with cirrhosis with refractory ascites and portal hypertensive bleeding. However, the indication for TIPS in older adult patients (greater than or equal to 70 years) is debated, and a specific prediction model developed in this particular setting is lacking. The aim of this study was to develop and validate a multivariable model for an accurate prediction of mortality in older adults., Approach and Results: We prospectively enrolled 411 consecutive patients observed at four referral centers with de novo TIPS implantation for refractory ascites or secondary prophylaxis of variceal bleeding (derivation cohort) and an external cohort of 415 patients with similar indications for TIPS (validation cohort). Older adult patients in the two cohorts were 99 and 76, respectively. A cause-specific Cox competing risks model was used to predict liver-related mortality, with orthotopic liver transplant and death for extrahepatic causes as competing events. Age, alcoholic etiology, creatinine levels, and international normalized ratio in the overall cohort, and creatinine and sodium levels in older adults were independent risk factors for liver-related death by multivariable analysis., Conclusions: After TIPS implantation, mortality is increased by aging, but TIPS placement should not be precluded in patients older than 70 years. In older adults, creatinine and sodium levels are useful predictors for decision making. Further efforts to update the prediction model with larger sample size are warranted., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background: Preterm extremely low birth weight infants (ELBWi) are known to be at greater risk of developing neuropsychiatric diseases. Identifying early predictors of outcome is essential to refer patients for early intervention. Few studies have investigated neurodevelopmental outcomes in Italian ELBWi. This study aims to describe neurodevelopmental outcome at 24 months of corrected age in an eleven-year single-center cohort of Italian ELBWi and to identify early risk factors for adverse neurodevelopmental outcomes., Methods: All infants born with birth weight < 1000 g and admitted to the Neonatal Intensive Care Unit of the "Fondazione IRCCS Policlinico San Matteo" hospital in Pavia, Italy, from Jan 1, 2005 to Dec 31, 2015 were eligible for inclusion. At 24 months, Griffiths' Mental Developmental Scales Extended Revised (GMDS-ER) were administered. Neurodevelopmental outcome was classified as: normal, minor sequelae (minor neurological signs, General Quotient between 76 and 87), major sequelae (cerebral palsy; General Quotient ≤ 75; severe sensory impairment). Univariate and multivariate multinomial logistic regression models were performed to analyze the correlation between neonatal variables and neurodevelopmental outcome., Results: 176 ELBWi were enrolled (mean gestational age 26.52 weeks sd2.23; mean birthweight 777.45 g sd142.89). 67% showed a normal outcome at 24 months, 17% minor sequelae and 16% major sequelae (4.6% cerebral palsy on overall sample). The most frequent major sequela was cognitive impairment (8.52%). In the entire sample the median score on the Hearing-Speech subscale was lower than the median scores recorded on the other subscales and showed a significantly weaker correlation to each of the other subscales of the GMDS-ER. Severely abnormal cUS findings (RRR 10.22 p 0.043) and bronchopulmonary dysplasia (RRR 4.36 p 0.008) were independent risk factors for major sequelae and bronchopulmonary dysplasia for minor sequelae (RRR 3.00 p 0.018) on multivariate multinomial logistic regression., Conclusions: This study showed an improvement in ELBWI survival rate without neurodevelopmental impairment at 24 months compared to previously reported international cohorts. Cognitive impairment was the most frequent major sequela. Median scores on GMDS-ER showed a peculiar developmental profile characterized by a selective deficit in the language domain. Severely abnormal cUS findings and bronchopulmonary dysplasia were confirmed as independent risk factors for major sequelae., (© 2022. The Author(s).)