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Background Vitamin D supplementation has shown promise for reducing mortality in the intensive care setting. As a steroid prohormone with pleiotropic effects, there may be a lag between administration and observing clinical benefit. This secondary analysis of the VITdAL-ICU study sought to explore whether the effect size of vitamin D on mortality was different when study participants who died or were discharged early were excluded. Methods The VITdAL-ICU study was a randomized, placebo-controlled trial in critically ill adults who received placebo or 540,000 IU cholecalciferol followed by monthly supplementation. The effect of vitamin D on 28-day mortality was evaluated after exclusion of participants who died or were discharged within 7 days from study drug administration, according to vitamin D concentrations on day 3, using a bivariate analysis adjusted for confounders and in a stepwise multiple analysis. Results Of 475 study participants, 65 died or were discharged within the first 7 days. In the remaining 410 patients, vitamin D supplementation was associated with a reduction in 28-day mortality [OR 0.58 (95% CI 0.35–0.97) p value = 0.035]. The effect on mortality was not significant after adjusting for age, severity scores, female gender, chronic liver and kidney disease, COPD, diagnosis of the tumor, mechanical ventilation, and vasopressors at enrollment (all p  > 0.05). In a multiple model, the mortality reduction by vitamin D supplementation did not remain independently significant [OR 0.61 (95% CI 0.35–1.05) p  = 0.075]. Vitamin D metabolite response, in the treatment group, demonstrated that survivors at 28 days, had higher levels of 25-hydroxyvitamin D (34.4 vs 25.4 ng/ml, p  = 0.010) and 1,25-dihydroxyvitamin D (107.6 vs 70.3 pg/ml, p  = 0.049) on day 3. The increase of plasma metabolites after vitamin D oral supplementation, independent of the baseline value, was associated with lower odds of death [OR 0.48 (95% CI 0.27–0.87) p value = 0.016]. Conclusions High-dose vitamin D3 supplementation was associated with a reduction of 28-day mortality in a mixed population of critically ill adults with vitamin D deficiency when excluding patients who died or were discharged within 7 days after study inclusion. However, this survival benefit was not independently confirmed when adjusted for other factors strongly associated with mortality.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, life-threatening lung disease with a global incidence of 0.09–1.30 per 10,000 individuals. Pirfenidone and nintedanib are the approved treatments for IPF. Objectives: This study evaluated the real-world safety and tolerability profiles of pirfenidone and nintedanib in IPF patients treated at the Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS ISMETT). A comparative analysis was conducted based on the number, types, and severity of adverse drug reactions (ADRs) and to identify potential predictors of treatment discontinuation or ADR onset based on patient characteristics. Design: A retrospective observational study was conducted on 531 IPF patients treated at IRCCS ISMETT with either pirfenidone or nintedanib. Methods: Eligible patients were selected based on the logged monthly dispensations provided by the pharmacy service for both therapies. Covariates were extracted from electronic medical records (age, sex, body mass index, smoking history, comorbidities, forced vital capacity (FVC) %, diffusing capacity of the lung for carbon monoxide (DLCO) %, 6-minute walk test (6-MWT), polytherapy, oxygen therapy, drug switch, etc.). ADRs were categorized by severity and follow-up status, and further classified according to the Medical Dictionary for Regulatory Activities, specifying the Preferred Terms and the related System Organ Classes. Chi-square or Fisher’s exact test was used for categorical variables, and univariate and multiple logistic regression identified potential risk factors for ADR onset. Backward Stepwise logistic regression (BSLR) was used to determine independent variables associated with ADR occurrence. Results: The nintedanib group had more frequent ADRs related to gastrointestinal and hepatobiliary disorders, with nausea, diarrhea, anorexia, and weight loss as the most common. The pirfenidone group had more ADRs related to skin, nervous system, and vascular disorders, such as rash, nausea, dizziness, and blood pressure imbalances. Significant baseline differences between groups included age, smoking status, FVC (%), DLCO (%), and 6-MWT, with the nintedanib cohort showing worse baseline characteristics. A total of 450 ADRs were reported: 59.6% for nintedanib and 40.4% for pirfenidone. Independent variables that significantly increased the likelihood of experiencing ADR were drug change, treatment type, gender, and age. Conclusion: Identifying ADR predictors is essential for personalizing treatment strategies. Both pirfenidone and nintedanib are crucial in managing IPF, highlighting the need for further research to optimize personalized therapies and patient outcomes. Plain language summary Safety, tolerability and predictive factors of ADRs in IPF treatment Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, interstitial and life-threatening lung disease classified as a rare disease. Two medications, pirfenidone and nintedanib, are approved to slow the progression of IPF, but both can cause side effects. This study aimed to compare these treatments and identify factors that might predict which patients are more likely to experience side effects. Researchers at IRCCS ISMETT analyzed the medical records of 531 patients with IPF treated with pirfenidone or nintedanib over a period of eight years starting from May 2014. They looked at factors such as age, smoking history, lung function, and other health conditions to understand how these might influence the likelihood of side effects. The study found that patients taking nintedanib were more likely to experience digestive issues like nausea, diarrhea, and weight loss. In contrast, patients on pirfenidone were more prone to skin rashes, dizziness, and changes in blood pressure. Overall, side effects were reported more frequently with nintedanib. Certain factors made side effects more likely: being older, taking nintedanib instead of pirfenidone, switching treatments, and gender, with men being less affected. The nintedanib group also had worse lung function at the start of treatment compared to the pirfenidone group. These findings underline the importance of tailoring treatment to each patient’s needs to reduce side effects and improve outcomes. Both pirfenidone and nintedanib remain vital for managing IPF, but further research is needed to enhance personalized care and improve quality of life for patients.

Background To evaluate incidence, risk factors, and outcomes of postoperative neurological complications in patients undergoing cardiac surgery. Methods A total of 2121 patients underwent cardiac surgery between August, 2008 and December, 2013; 91/2121 (4.3%) underwent brain computed tomography (70/91, 77%) or magnetic resonance imaging (21/91, 23%) scan because of major stroke (37/2121, 1.7%) and a spectrum of transient neurological episodes as well as transient ischemic attacks and delirium /psychosis/seizures (54/2121, 2.5%). The mean age was 65.3 ± 12.1 years and 60 (65.9%) were male. Variables were compared among study- and matched-patients ( n  = 113) without neurological deficits. Results A total of 37/2121 (1.7%) patients had imaging evidence of stroke. Radiological examinations were done 5.72 ± 3.6 days after surgery. Patients with and without imaging evidence of stroke had longer intensive care unit length of stay (LOS) (13.8 ± 14.7 and 12.9 ± 15 days vs. 5.7 ± 12.1 days, respectively ( p  < 0.001) and hospital LOS (53 ± 72.8 and 35.5 ± 29.8 days vs. 18.4 ± 29.2 days, respectively (p < 0.001) than the control group. The hospital mortality of patients with and without imaging evidence of stroke was higher than the control group (7/37 patients [19%], and 12/54 patients [22%] vs. 4/115 patients [3%], respectively (p < 0.001). Multivariate analysis showed that bilateral internal carotid artery stenosis of any grade ( p  < .001), and re-do operations ( p  = .013) increased the risk of postoperative neurological complications. Conclusions Neurological complications after cardiac surgery increase hospitalization and mortality even in patients without radiologic evidence of stroke. Bilateral internal carotid artery stenosis of any grade, suggesting a diffuse patient propensity toward atherosclerosis, and re-do operations increase the risk of postoperative neurological complications.

Hepatitis C virus (HCV) predominantly infects hepatocytes, although it is known that receptors for viral entry are distributed on a wide array of target cells. Chronic HCV infection is indeed characterized by multiple non-liver manifestations, suggesting a more complex HCV tropism extended to extrahepatic tissues and remains to be fully elucidated. In this study, we investigated the gastrointestinal mucosa (GIM) as a potential extrahepatic viral replication site and its contribution to HCV recurrence. We analyzed GIM biopsies from a cohort of 76 patients, 11 of which were HCV-negative and 65 HCV-positive. Of these, 54 biopsies were from liver-transplanted patients. In 29 cases, we were able to investigate gastrointestinal biopsies from the same patient before and after transplant. To evaluate the presence of HCV, we looked for viral antigens and genome RNA, whilst to assess viral replicative activity, we searched for the replicative intermediate minus-strand RNA. We studied the genetic diversity and the phylogenetic relationship of HCV quasispecies from plasma, liver and gastrointestinal mucosa of HCV-liver-transplanted patients in order to assess HCV compartmentalization and possible contribution of gastrointestinal variants to liver re-infection after transplantation. Here we show that HCV infects and replicates in the cells of the GIM and that the favorite hosts were mostly enteroendocrine cells. Interestingly, we observed compartmentalization of the HCV quasispecies present in the gastrointestinal mucosa compared to other tissues of the same patient. Moreover, the phylogenetic analysis revealed a high similarity between HCV variants detected in gastrointestinal mucosa and those present in the re-infected graft. Our results demonstrated that the gastrointestinal mucosa might be considered as an extrahepatic reservoir of HCV and that could contribute to viral recurrence. Moreover, the finding that HCV infects and replicates in neuroendocrine cells opens new perspectives on the role of these cells in the natural history of HCV infection.

The use of extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome (ARDS) has increased in the last decade. However, mortality remains high, and the complexity of ECMO requires individualized treatment. There are some biomarkers to monitor progression and predict clinical outcomes of ARDS. This project aims to advance the management of ARDS patients treated with ECMO by exploring miRNA expression in whole blood. The analysis was conducted on two groups with different length of ECMO: Group A (longer runs) and group B (shorter runs). We analyzed miRNAs before ECMO cannulation, and at 7 and 14 days of ECMO support. Our results showed that in the group B patients, 11 deregulated miRNAs were identified, and showed an opposite trend of expression compared to the group A patients. In silico analysis revealed that these 11 miRNAs were related to processes involved in the pathogenesis and evolution of ARDS. This scenario could represent homeostatic mechanisms by which, in ECMO responsive patients, pathways activated during ARDS progression are switched-off. Circulating miRNAs could represent promising biomarkers to monitor the evolution of ARDS under ECMO support. Further studies may shed light on this topic to improve a personalized approach in such a complex setting of patients.

The retrieval and transport of patients from peripheral hospitals to high volume extracorporeal membrane oxygenation (ECMO) centers aims to reduce complications and improve survival. In Sicily (Italy), our institute houses a mobile ECMO team that serves a population of around 10 million people for a vast area in southern Italy and Malta. This observational, descriptive study includes all patients that required veno–venous (V-V) ECMO and transport by a mobile team between October 2009 and May 2020. Linear and multiple logistic regressions were applied to explore the risk factors for mortality in the ICU. Kaplan–Meier estimates were generated to predict the survival in patients transported by helicopter or ambulance, and the two cohorts were compared according to their baseline characteristics. Of 122 patients transported, 89 (73%) survived to ICU discharge (50 (41%) patients were transported by ambulance, and 72 (59%) were transported by helicopter). Independent predictive factors associated with mortality in a stepwise multiple regression model were prone positioning, acute kidney injury, and the number of days spent on mechanical ventilation (MV). Kaplan–Meier estimates for survival favored the helicopter cohort (79%) rather than the ambulance cohort (64%). Patients transported by helicopter had better pre-ECMO profiles, with shorter hospital and ICU stays, a shorter duration of MV use, and higher RESP scores, which indicate better survival probabilities. ECMO transport can be carried out safely over long distances; in rural areas with underdeveloped roads, transportation via helicopter or ambulance can extend the arm of the hospital to remote areas. Early ECMO initiation can be crucial in improving survival outcomes, and when transportation is the limiting factor to starting ECMO support, it should be attempted at the earliest logistical stage possible.

There is a need to improve acute respiratory distress syndrome (ARDS) diagnosis and management, particularly with extracorporeal membrane oxygenation (ECMO), and different biomarkers have been tested to implement a precision-focused approach. We included ARDS patients on veno-venous (V-V) ECMO in a prospective observational pilot study. Blood samples were obtained before cannulation, and screened for the expression of 754 circulating microRNA (miRNAs) using high-throughput qPCR and hierarchical cluster analysis. The miRNet database was used to predict target genes of deregulated miRNAs, and the DIANA tool was used to identify significant enrichment pathways. A hierarchical cluster of 229 miRNAs (identified after quality control screening) produced a clear separation of 11 patients into two groups: considering the baseline SAPS II, SOFA, and RESP score cluster A (n = 6) showed higher severity compared to cluster B (n = 5); p values < 0.05. After analysis of differentially expressed miRNAs between the two clusters, 95 deregulated miRNAs were identified, and reduced to 13 by in silico analysis. These miRNAs target genes implicated in tissue remodeling, immune system, and blood coagulation pathways. The blood levels of 13 miRNAs are altered in severe ARDS. Further investigations will have to match miRNA results with inflammatory biomarkers and clinical data.

Background: Cerebral small vessels disease (cSVD) is an age-related disorder and risk factor for stroke and cognitive/motor impairments. Neurological complications (NCs) are among the causes of adverse outcomes in older liver transplant recipients. This study sought to determine whether cSVD predicts acute NCs in over 65-year-old liver transplant patients. Methods: Data were collected, from a retrospective medical chart review, of 22 deceased donor liver transplant recipients aged 65 years or older with a pre-operative brain magnetic resonance imaging (MRI). We used the Fazekas score (0–3) as a quantitative measurement of the vascular lesion load seen in the MRI. We analyzed all post-operative acute NCs occurring during the hospital stay and any other non-NC. Results: cSVD was recognized in all patients. Neurological complications (NCs) occurred in 18.1% of patients with toxic-metabolic encephalopathy the most frequent diagnosis (13.64%). More severe cSVD was associated with seizures (p = 0.0362), longer hospital stay (p 0.0299), and disability (p 0.0134). In our elderly cohort, hepatic encephalopathy (HE) (p 0.0287) and ascites (p 0.0270) were predictors of NCs after liver transplantation. Ascites and/or variceal bleeding and severity of liver disease were associated with adverse post-operative outcomes. The small sample size limited the statistical analysis power. Conclusions: We present the preliminary data of a single-center retrospective study aimed at understanding the cSVD role on NCs and non-NCs after a liver transplantation in elderly patients. This would encourage a more appropriate multicenter prospective study that will definitely confirm if a neurological screening in old age liver transplant candidates is appropriate.

Background Liver transplantation is the best treatment for end-stage liver disease. The interruption of the blood supply to the donor liver during cold storage damages the liver, affecting how well the liver will function after transplant. The drug Simvastatin may help to protect donor livers against this damage and improve outcomes for transplant recipients. The aim of this study is to evaluate the benefits of treating the donor liver with Simvastatin compared with the standard transplant procedure. Patient and methods We propose a prospective, double-blinded, randomized phase 2 study of 2 parallel groups of eligible adult patients. We will compare 3-month, 6-month, and 12-month graft survival after LT, in order to identify a significant relation between the two homogenous groups of LT patients. The two groups only differ by the Simvastatin or placebo administration regimen while following the same procedure, with identical surgical instruments, and medical and nursing skilled staff. To reach these goals, we determined that we needed to recruit 106 patients. This sample size achieves 90% power to detect a difference of 14.6% between the two groups survival using a one-sided binomial test. Discussion This trial is designed to confirm the effectiveness of Simvastatin to protect healthy and steatotic livers undergoing cold storage and warm reperfusion before transplantation and to evaluate if the addition of Simvastatin translates into improved graft outcomes. Trial registration ISRCTN27083228 .

Purpose To retrospectively compare outcomes of TIPS performed by puncturing left portal vein (LPV) vs right portal vein (RPV) to access the portal system. Materials and methods One hundred ninety-three consecutive patients underwent TIPS with controlled expansion covered stent by using the LPV (37 patients) or the RPV (156 patients). Patients were followed until the last clinical evaluation, liver transplantation, or death. Results Demographics and clinical characteristics of the two groups were comparable. The median follow-up was 9.6 months (range 0.1–50.6). Portosystemic pressure gradient (PSG) before TIPS 15.7 mmHg ± 4.7 in RPV group (RPVG) vs 15.4 mmHg ± 4.5 in LPV group (LPVG) ( p = 0.725). After TIPS, PSG 6.3 mmHg ± 2.8 in RPVG vs 6.2 mmHg ± 2.2 ( p = 0.839). In LPVG, the stent was dilated to 8-mm in 95% of patients vs 77% of RPVG ( p = 0.015). Two (5.4%) and 22 (14%) patients underwent TIPS revision in LPVG and RPVG ( p = 0.15). The incidence of overt HE was 13% in LPVG and 24% in RPVG ( p = 0.177). Rebleeding occurred in 3 of 49 patients (6%) with variceal bleeding as an indication: 2/41 patients (4.9%) in RPVG vs 1/8 patients (12.5%) in LPVG ( p = 0.417). Among 126 patients with refractory ascites 20 patients (15.9%) needed paracentesis 3 months after the procedure: 18/101 patients (17.8%) in RPVG vs 2/25 patients (8%) in LPVG ( p = 0.231). Thirty-seven patients (19%) died: 32 (21%) in RPVG and 5 (14%) in LPVG ( p = 0.337). Conclusion Compared with RPV puncture, in TIPS created through the LPV, the targeted PSG was reached with a smaller stent diameter. However, no significant difference in clinical outcomes was observed. Key Points • A LPV approach for TIPS creation does not lead to better control of complications of portal hypertension as compared to a RPV approach .