Gold nanoparticles for the in situ polymerization of near-infrared responsive hydrogels based on fibrin.

Non-invasiveness and relative safety of photothermal therapy, which enables local hyperthermia of target tissues using a near infrared (NIR) laser, has attracted increasing interest. Due to their biocompatibility, amenability of synthesis and functionalization, gold nanoparticles have been investigated as therapeutic photothermal agents. In this work, hollow gold nanoparticles (HGNP) were coated with poly-l-lysine through the use of COOH-Poly(ethylene glycol)-SH as a covalent linker. The functionalized HGNP, which peak their surface plasmon resonance at 800 nm, can bind thrombin. Thrombin-conjugated HGNP conduct in situ fibrin polymerization, facilitating the process of generating photothermal matrices. Interestingly, the metallic core of thrombin-loaded HGNP fragmentates at physiological temperature. During polymerization process, matrices prepared with thrombin-loaded HGNP were loaded with genetically-modified stem cells that harbour a heat-activated and ligand-dependent gene switch for regulating transgene expression. NIR laser irradiation of resulting cell constructs in the presence of ligand successfully triggered transgene expression in vitro and in vivo. STATEMENT OF SIGNIFICANCE: Current technological development allows synthesis of gold nanoparticles (GNP) in a wide range of shapes and sizes, consistently and at scale. GNP, stable and easily functionalized, show low cytotoxicity and high biocompatibility. Allied to that, GNP present optoelectronic properties that have been exploited in a range of biomedical applications. Following a layer-by-layer functionalization approach, we prepared hollow GNP coated with a positively charged copolymer that enabled thrombin conjugation. The resulting nanomaterial efficiently catalyzed the formation of fibrin hydrogels which convert energy of the near infrared (NIR) into heat. The resulting NIR-responsive hydrogels can function as scaffolding for cells capable of controlled gene expression triggered by optical hyperthermia, thus allowing the deployment of therapeutic gene products in desired spatiotemporal frameworks.

Patient safety in external beam radiotherapy, results of the ACCIRAD project: Recommendations for radiotherapy institutions and national authorities on assessing risks and analysing adverse error-events and near misses.

The ACCIRAD project, commissioned by the European Commission (EC) to develop guidelines for risk analysis of accidental and unintended exposures in external beam radiotherapy (EBRT), was completed in the year 2014. In 2015, the "General guidelines on risk management in external beam radiotherapy" were published as EC report Radiation Protection (RP)-181. The present document is the third and final report of the findings from the ACCIRAD project. The main aim of this paper is to describe the key features of the risk management process and to provide general guidelines for radiotherapy departments and national authorities on risk assessment and analysis of adverse error-events and near misses. The recommendations provided here and in EC report RP-181 are aimed at promoting the harmonisation of risk management systems across Europe, improving patient safety, and enabling more reliable inter-country comparisons.

Association of Cardiac Abnormalities to the Frail Phenotype in Cirrhotic Patients on the Waitlist: From the Functional Assessment in Liver Transplantation Study.

BACKGROUND: Frailty is a syndrome of decreased physiologic reserve that results from compromise of multiple physiologic systems including cardiovascular system. We aimed to determine the association between the frail phenotype and cardiac abnormalities in liver transplant (LT) candidates through evaluation of transthoracic echocardiography (TTE) indices. METHODS: Included were consecutive outpatients listed for LT who underwent a frailty assessment from January 1, 2014, to June 30, 2016 (using the Liver Frailty Index) and a 2-dimensional/Doppler TTE examination. Patients were categorized as robust, intermediate frail, or frail by the Liver Frailty Index based on scores of less than 3.2, between 3.2 and 4.5, or 4.5 or greater. Linear regression assessed associations between the Liver Frailty Index and TTE indices. RESULTS: Of 335 patients, 19% were robust, 65% intermediate frail, and 16% frail. TTE indices of left atrial (LA) dilatation differed significantly by frailty status: median LA dimension (P = 0.03), LA volume index (LAVI mL/m; P < 0.001) and %LAVI > 34 mL/m (P = 0.001). In linear regression adjusted for age, sex, hypertension, and diabetes, the Liver Frailty Index was positively associated with LA dimension (coeff, 0.20; 95% confidence interval [CI], 0.07-0.34), LAVI mL/m (coeff, 0.01; 95% CI, 0.005-0.02), ejection fraction (coeff, 1.59; 95% CI, 0.32-2.85), and pulmonary artery systolic pressure (coeff, 0.01; 95% CI, 0.003-0.02), and negatively associated with LV hypertrophy (coeff, -0.22; 95% CI, -0.37 to -0.06). CONCLUSIONS: In LT candidates, frailty is associated with cardiac structural and functional changes, independent of known risk factors. Our study provides evidence to support that measures of frailty in cirrhotic patients encompass abnormalities of the cardiovascular system and may inform assessments of cardiovascular reserve in this population.

Tenofovir vs lamivudine plus adefovir in chronic hepatitis B: TENOSIMP-B study.

AIM: To demonstrate the non-inferiority (15% non-inferiority limit) of monotherapy with tenofovir disoproxil fumarate (TDF) vs the combination of lamivudine (LAM) plus adefovir dipivoxil (ADV) in the maintenance of virologic response in patients with chronic hepatitis B (CHB) and prior failure with LAM. METHODS: This study was a Phase IV prospective, randomized, open, controlled study with 2 parallel groups (TDF and LAM+ADV) of adult patients with hepatitis B e antigen (HBeAg)-negative CHB, prior failure with LAM, on treatment with LAM+ADV for at least 6 mo, without prior resistance to ADV and with an undetectable viral load at the start of the study, in 14 Spanish hospitals. The follow-up time for each patient was 48 wk after randomization, with quarterly visits in which the viral load, biochemical and serological parameters, adverse effects, adherence to treatment and consumption of hospital resources were analysed. RESULTS: Forty-six patients were evaluated [median age: 55.4 years (30.2-75.2); 84.8% male], including 22 patients with TDF and 24 with LAM+ADV. During study development, hepatitis B virus DNA (HBV-DNA) remained undetectable, all patients remained HBeAg negative, and hepatitis B surface antigen (HBsAg) positive. Alanine aminotransferase (ALT) values at the end of the study were similar in the 2 groups (25.1 ± 7.65, TDF vs 24.22 ± 8.38, LAM+ADV, P = 0.646). No significant changes were observed in creatinine or serum phosphorus values in either group. No significant differences between the 2 groups were noted in the identification of adverse effects (AEs) (53.8%, TDF vs 37.5%, LAM+ADV, P = 0.170), and none of the AEs which occurred were serious. Treatment adherence was 95.5% and 83.3% in the TDF and the LAM+ADV groups, respectively (P = 0.488). The costs associated with hospital resource consumption were significantly lower with the TDF treatment than the LAM+ADV treatment (€4943 ± 1059 vs €5811 ± 1538, respectively, P < 0.001). CONCLUSION: TDF monotherapy proved to be safe and not inferior to the LAM+ADV combination therapy in maintaining virologic response in patients with CHB and previous LAM failure. In addition, the use of TDF generated a significant savings in hospital costs.

Patient safety in external beam radiotherapy, results of the ACCIRAD project: Current status of proactive risk assessment, reactive analysis of events, and reporting and learning systems in Europe.

PURPOSE: To describe the current status of implementation of European directives for risk management in radiotherapy and to assess variability in risk management in the following areas: 1) in-country regulatory framework; 2) proactive risk assessment; (3) reactive analysis of events; and (4) reporting and learning systems. MATERIAL AND METHODS: The original data were collected as part of the ACCIRAD project through two online surveys. RESULTS: Risk assessment criteria are closely associated with quality assurance programs. Only 9/32 responding countries (28%) with national regulations reported clear "requirements" for proactive risk assessment and/or reactive risk analysis, with wide variability in assessment methods. Reporting of adverse error events is mandatory in most (70%) but not all surveyed countries. CONCLUSIONS: Most European countries have taken steps to implement European directives designed to reduce the probability and magnitude of accidents in radiotherapy. Variability between countries is substantial in terms of legal frameworks, tools used to conduct proactive risk assessment and reactive analysis of events, and in the reporting and learning systems utilized. These findings underscore the need for greater harmonisation in common terminology, classification and reporting practices across Europe to improve patient safety and to enable more reliable inter-country comparisons.

Use of artificial intelligence as an innovative donor-recipient matching model for liver transplantation: results from a multicenter Spanish study.

BACKGROUND & AIMS: There is an increasing discrepancy between the number of potential liver graft recipients and the number of organs available. Organ allocation should follow the concept of benefit of survival, avoiding human-innate subjectivity. The aim of this study is to use artificial-neural-networks (ANNs) for donor-recipient (D-R) matching in liver transplantation (LT) and to compare its accuracy with validated scores (MELD, D-MELD, DRI, P-SOFT, SOFT, and BAR) of graft survival. METHODS: 64 donor and recipient variables from a set of 1003 LTs from a multicenter study including 11 Spanish centres were included. For each D-R pair, common statistics (simple and multiple regression models) and ANN formulae for two non-complementary probability-models of 3-month graft-survival and -loss were calculated: a positive-survival (NN-CCR) and a negative-loss (NN-MS) model. The NN models were obtained by using the Neural Net Evolutionary Programming (NNEP) algorithm. Additionally, receiver-operating-curves (ROC) were performed to validate ANNs against other scores. RESULTS: Optimal results for NN-CCR and NN-MS models were obtained, with the best performance in predicting the probability of graft-survival (90.79%) and -loss (71.42%) for each D-R pair, significantly improving results from multiple regressions. ROC curves for 3-months graft-survival and -loss predictions were significantly more accurate for ANN than for other scores in both NN-CCR (AUROC-ANN=0.80 vs. -MELD=0.50; -D-MELD=0.54; -P-SOFT=0.54; -SOFT=0.55; -BAR=0.67 and -DRI=0.42) and NN-MS (AUROC-ANN=0.82 vs. -MELD=0.41; -D-MELD=0.47; -P-SOFT=0.43; -SOFT=0.57, -BAR=0.61 and -DRI=0.48). CONCLUSIONS: ANNs may be considered a powerful decision-making technology for this dataset, optimizing the principles of justice, efficiency and equity. This may be a useful tool for predicting the 3-month outcome and a potential research area for future D-R matching models.

Prospective validation of a noninvasive index for predicting liver fibrosis in hepatitis C virus-infected liver transplant recipients.

We previously developed a mathematical model, the Hospital Universitario La Fe (HULF) index, as an alternative to protocol liver biopsy (PLB) to estimate significant fibrosis (SF) in patients who underwent liver transplantation (LT) for liver damage caused by chronic HCV infection. In the present study, we sought to validate this noninvasive index. The commonly derived clinical and laboratory data for calculating the HULF index were prospectively collected over 2.7 years from patients undergoing LT and PLB. The sensitivity, specificity, positive and negative predictive values, and diagnostic capacity were evaluated with receiver operating characteristic curve analysis. Biopsy was performed 93 times in 86 LT patients. The prevalence of SF (F3-F4 on the Knodell scoring system) was 32%. The intraobserver and interobserver concordance was high (kappa = 0.94 and kappa = 0.75, respectively) in identifying SF in PLB. For low scores, the HULF index discarded an SF diagnosis with a sensitivity of 90% and a negative predictive value of 89%. The area under the receiver operating characteristic curve was 0.68. The precision of the HULF index did not improve with the incorporation of donor age and body mass index into the multivariate analysis. Applying the index would have prevented 24% of the biopsy procedures performed. In conclusion, the HULF index was prospectively validated with data commonly obtained in standard clinical practice. Because the index distinguishes a subgroup of HCV LT patients with a low probability of having SF, PLB would be avoided in those patients.

[Adefovir dipivoxil compassionate use program in Spain: efficacy and resistance analysis]. / Programa de uso compasivo con adefovir dipivoxil en España: valoración de su eficacia y estudio de las resistencias.

BACKGROUND AND OBJECTIVE: The extended treatment with lamivudine in patients with chronic hepatitis B is associated with the emergence of resistances. Patients with resistance to lamivudine show a loss of biochemical and virological responses and a higher progression of their liver disease. Adefovir dipivoxil, an analogue of the nucleotides, is effective for the treatment of patients with resistance to lamivudine. The aim of this study was to evaluate the efficacy, safety and resistance of adefovir dipivoxil in patients with chronic hepatitis B refractory to treatment with lamivudine. PATIENTS AND METHOD: One hundred and twenty hepatits B virus patients refractory to lamivudine were treated with adefovir dipivoxil. Seventy-four patients were followed up during two years. In all cases, the hepatitis B virus-DNA was determined by polymerase chain reaction, and in those cases without response to treatment, the presence of resistances to adefovir and lavimudine were studied. RESULTS: At the second year of treatment, we observed a biological response of 54.1%, a biochemical response of 62.2%, while an elimination of hepatitis B e antigen was seen in 21% cases. 20% patients developed resistance to adefovir dipivoxil, and the most frequent detected mutations were: A181V, A181T and N236T. Drug safety was excellent; in fact, only one adverse effect related to the drug was detected. CONCLUSIONS: Treatment with adefovir dipivoxil for 2 years in mono-therapy in patient who are previously non-responders to lavimudine is associated with a high biochemical and virologycal response with an excellent safety. At the second year of treatment, the adefovir dipivoxil resistance rate is 20%.

[Liver retransplantation: outcome analysis in 50 patients]. / Retrasplante hepático: análisis de los resultados en 50 pacientes.

BACKGROUND AND OBJECTIVE: Liver re-transplantation (re-LT) is an accepted indication for some (technical problems, primary non-function [PNF]) but not all indications, particularly recurrence of the original disease, such as hepatitis C. We aimed to determine in our center: a) the rate of survival following re-transplantation for all and each different indication; b) to compare it to that obtained by a control group; c) to assess whether late re-LT, excluding PNF and surgical problems, and re-LT in HCV (+) patients are associated with a higher mortality, and d) to estimate medical costs. PATIENTS AND METHOD: Form 1991 to April 2002, 50 re-LT were done (group 1). Group 2 consisted of 45 primary LT controlled by transplant date. Group 1 was divided in two subgroups: a) re-LT after 6 months of the first LT (recurrence of primary liver disease n = 20, chronic rejection n = 5), b) Re-LT in the first 6 months (PNF n = 13, artery thrombosis n = 12). We analyzed donor, recipient, surgical and immunosuppressive-related variables. RESULTS: The mean age was 50 years (range: 23-63) (72% men). Actuarial survival for re-LT was lower than for the control group: 64%, 57% and 50% vs 84%, 82% and 82% at 1st, 3rd and 5th year, respectively. By indication, the 3-year survival was: PNF: 61% (p = 0.05), HAT: 58% (p = 0.02), recurrence of primary disease: 52% (p = 0.001), chronic rejection: 60% (p = 0.346). Although not reaching statistical significance, survival was lower in late vs early re-LT (p = 0.16) and in HCV-infected versus non-infected patients (p = 0.08). In the HCV (+) group, there were no differences by re-transplant indication (p = 0.8). Medical costs and complications were substantially higher in group 1 vs group 2. CONCLUSIONS: Re-LT is associated with substantial medical costs and mortality, particularly in patients infected with HCV.

A randomized study comparing lamivudine monotherapy after a short course of hepatitis B immune globulin (HBIg) and lamivudine with long-term lamivudine plus HBIg in the prevention of hepatitis B virus recurrence after liver transplantation.

BACKGROUND/AIMS: To compare the efficacy in preventing hepatitis B virus (HBV) recurrence of lamivudine vs. lamivudine plus hepatitis B immune globulin (HBIg) after a short course of HBIg and lamivudine in liver transplanted chronic hepatitis B patients. METHODS: Forty-six patients with HBV cirrhosis received lamivudine before liver transplantation and were then randomized to receive lamivudine plus HBIg for 1 month followed by lamivudine or both drugs for 17 months. RESULTS: Thirty-two patients were transplanted and 29 were randomized to receive combination therapy (15 cases) or lamivudine monotherapy (14 cases). HBV DNA was undetectable in all cases (17 induced by lamivudine therapy) at the time of liver transplantation. After 18 months of follow-up, all patients survived without HBV recurrence: hepatitis Bs antigen and HBV DNA were negative; however, HBV DNA was detected by polymerase chain reaction in four cases (three with HBIg plus lamivudine and one with lamivudine). Alanine aminotransferase levels were normal except in six cases (one HCV and two HDV coinfections). There were no drug-related adverse events. CONCLUSIONS: Lamivudine monotherapy after a short course of lamivudine and HBIg is equally as efficacious in preventing HBV recurrence as HBIg plus lamivudine during the first 18 months after liver transplantation. This strategy is more economic and convenient to administer than long-term HBIg plus lamivudine.