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The energetically most favorable chemical ordering of bimetallic nanoparticles can be characterized by combining global optimization algorithms and surrogate energy models. The latter approximate the energy of nanoalloys relying on structural descriptors, training models, and data. Here, we systematically evaluate the performance of highly data-efficient topological descriptors [Kozlov et al., Chem. Sci. 6, 3868 (2015)] for predicting the energies of metal nanoalloys with different chemical orderings. We also introduce a new descriptor based on atomic coordination types, which results in a less data-efficient and interpretable approach, but improves the general accuracy and the quantification of orderings in the inner parts of nanoparticles. The capacity of both the original and new approaches in combination with a basin hopping algorithm is illustrated by generating convex hulls of PdZn nanoalloys and predicting the resulting active surface site distribution as a function of particle composition. Finally, we show how these approaches can be combined with machine-learning adsorption models in electrocatalysis studies for a fast evaluation of the reactivity landscape of targeted nanoalloys. [ABSTRACT FROM AUTHOR]

Pt-based alloys, such as Pt3Ni, are among the best electrocatalysts for oxygen reduction reaction (ORR) in polymer electrolyte membrane fuel cells. Doping of PtNi alloys with Zr was shown to enhance the durability of the operating ORR catalysts. Rationalizing these observations is hindered by the absence of atomic-level data for these tri-metallic materials, even when not exposed to the fuel cell operation conditions. This study aims at understanding structure–property relations in Zr-doped PtNi nanoparticles as a key to their ORR function. In particular, we calculated, using a method based on density functional theory, the most stable chemical orderings of pristine and Zr-doped Pt3Ni particles containing over 400 atoms. We thus clarify (i) preferential location and charge states of Zr atoms in the Pt3Ni NPs; (ii) effect of doping Zr atoms on the stability of the Pt skin of the Pt3Ni NPs; (iii) charge redistribution induced by Zr dopants; (iv) layer-by-layer atomic ordering in the Pt3Ni/Zr NPs with the increasing Zr content; and (v) effect of Zr atoms on the adsorption energies of O and OH species as indicators of the ORR activity. [ABSTRACT FROM AUTHOR]

Background and Objectives: Direct-acting antivirals (DAAs) offer a high rate of hepatitis C virus (HCV) eradication. However, concerns on the risk of cancer after HCV eradication remain. Our study aimed at quantifying the incidence of cancer in patients treated with anti-HCV therapies in Catalonia (Spain) and their matched controls. Methods: This was a population-based study using real-world data from the public healthcare system of Catalonia between 2012 and 2016. Propensity score matching was performed in patients with HCV infection treated with interferon-based therapy (IFN), sequential IFN and DAA (IFN+DAA), and DAA only (DAA) with concurrent controls. We estimated the annual incidence of overall cancer, hepatocellular carcinoma, and non-liver cancer of HCV-treated patients and their corresponding rate ratios. Results: The study included 11,656 HCV-treated patients and 49,545 controls. We found statistically significant increases in the rate of overall cancer for IFN+DAA-treated (rate ratio [RR] 1.77, 95% confidence interval [CI] 1.27–2.46) and DAA-treated patients (RR 1.90, 95% CI 1.66–2.19) and in the rate of HCC for IFN-treated (RR 1.50, 95% CI 1.02–2.22), IFN+DAA-treated (RR 3.89, 95% CI 2.26–6.69), and DAA-treated patients (RR 6.45, 95% CI 4.90–8.49) compared with their corresponding controls. Moreover, DAA-treated patients with cirrhosis showed an increased rate of overall cancer versus those without cirrhosis (RR 1.92, 95% CI 1.51–2.44). Conclusions: Results showed that overall cancer and hepatocellular carcinoma incidence in Catalonia was significantly higher among HCV-treated patients compared with matched non-HCV-infected controls, and risks were higher in patients with cirrhosis. An increased awareness of the potential occurrence of uncommon malignant events and monitoring after HCV eradication therapy may benefit patients. Plain Language Summary: Direct-acting antivirals (DAAs) are effective drugs for eradicating hepatitis C virus (HCV). However, concerns about the risk of cancer after HCV eradication remain. Therefore, this study aimed to compare the incidence of cancer between patients treated with anti-HCV therapies in Catalonia (Spain) and properly matched, non-HCV-infected individuals (controls). This study was based on real-world data from the public healthcare system of Catalonia, specifically from patients with HCV infection treated with interferon-based therapy (IFN), sequential IFN and DAA (IFN+DAA), or DAA only (DAA). We calculated the incidence and rate ratios of overall cancer and hepatocellular carcinoma of HCV-treated patients. We observed that the rate of overall cancer increased in patients receiving DAA or IFN+DAA, whereas the rate of hepatocellular carcinoma increased in all groups of HCV-treated patients. Of note, DAA-treated patients with cirrhosis showed an increased rate of overall cancer versus those without cirrhosis. Thus, a close monitoring for detection of cancer in patients after HCV eradication seems reasonable, especially in those with cirrhosis. [ABSTRACT FROM AUTHOR]

Background: The risk of hepatocarcinoma in HCV cirrhotic patient responders after treatment with DAAs decrease, but HCC still occurs. A correlation between specific miRNAs and the development of hepatocarcinoma have been highlighted. Aim: To investigate miRNA expression in HCV-infected cirrhotic patients treated with DAAs, regarding whether or not they developed HCC at follow-up. Methods: A total of 73 outpatients with HCV-related cirrhosis treated with DAAs were enrolled, 28 of which had HCC. Samples were collected at the start and at the end of treatment. In the screening phase, 172 miRNAs were analyzed at baseline. Differentially expressed miRNAs were validated in the entire cohort. Results: In the validation phase, at baseline and in patients treated for 12 weeks, miR-28-5p was confirmed to be more highly expressed in the HCC group compared to the non-HCC group. In all of the patients treated for 12 weeks, at end of the treatment we found a significant downregulation in miR-132-3p, miR-133b-3p, miR-221-3p and miR-324-3p. In the HCC group, miR-28-5p was significantly downregulated after DAA therapy as well as in HCC patients treated for 24 weeks. Conclusion: In the HCC group, miR28-5p was differently expressed both at baseline and at the end of therapy with DAAs. This difference in expression should suggest its involvement in HCC development. [ABSTRACT FROM AUTHOR]

Nanostructured materials based on CeO2 and Pt play a fundamental role in catalyst design. However, their characterization is often challenging due to their structural complexity and the tendency of these materials to change under reaction conditions. In this work, we combine calculations based on the density functional theory, a machine-learning assisted global optimization method, and ab initio thermodynamics to characterize stable oxidation states of ceria-supported PtyOx particles under different environmental conditions. The collection of global minima structures for different stoichiometries resulting from the global optimization effort is used to assess the effect of temperature, oxygen pressure, and support interactions on the phase diagrams, oxidation states, and geometries of the PtyOx particles. We, thus, identify favored structural motifs and O:Pt ratios, revealing that oxidized states of freestanding and ceria-supported platinum particles are more stable than reduced ones under a wide range of conditions. These results indicate that studies rationalizing activity of ceria-supported Pt clusters must consider oxidized states and that previous understanding of such materials obtained only with fully reduced Pt clusters may be incomplete. [ABSTRACT FROM AUTHOR]

Background & aims: Metallothionein-3 (hMT3) is a structurally unique member of the metallothioneins family of low-mass cysteine-rich proteins. hMT3 has poorly characterized functions, and its importance for hepatocellular carcinoma (HCC) cells has not yet been elucidated. Therefore, we investigated the molecular mechanisms driven by hMT3 with a special emphasis on susceptibility to sorafenib. Methods: Intrinsically sorafenib-resistant (BCLC-3) and sensitive (Huh7) cells with or without up-regulated hMT3 were examined using cDNA microarray and methods aimed at mitochondrial flux, oxidative status, cell death, and cell cycle. In addition, in ovo/ex ovo chick chorioallantoic membrane (CAM) assays were conducted to determine a role of hMT3 in resistance to sorafenib and associated cancer hallmarks, such as angiogenesis and metastastic spread. Molecular aspects of hMT3-mediated induction of sorafenib-resistant phenotype were delineated using mass-spectrometry-based proteomics. Results: The phenotype of sensitive HCC cells can be remodeled into sorafenib-resistant one via up-regulation of hMT3. hMT3 has a profound effect on mitochondrial respiration, glycolysis, and redox homeostasis. Proteomic analyses revealed a number of hMT3-affected biological pathways, including exocytosis, glycolysis, apoptosis, angiogenesis, and cellular stress, which drive resistance to sorafenib. Conclusions: hMT3 acts as a multifunctional driver capable of inducing sorafenib-resistant phenotype of HCC cells. Our data suggest that hMT3 and related pathways could serve as possible druggable targets to improve therapeutic outcomes in patients with sorafenib-resistant HCC. [ABSTRACT FROM AUTHOR]

Introduction: The incidence of hepatocellular carcinoma (HCC) in Budd-Chiari syndrome (BCS) is unknown and there is no validated diagnostic work-up to define the liver nodules with arterial phase hyperenhancement (APHE), suggesting malignancy. This prospective study evaluates HCC incidence in a Western cohort of patients with BCS and assesses the performance of MRI with hepatobiliary contrast (HB-MRI) for nodule characterization. Methods: Patients with BCS followed in our hospital were prospectively evaluated by MRI with extracellular contrast (EC-MRI). Nodules with APHE categorized as non-conclusively benign by 2 radiologists were studied by HB-MRI and reviewed by 2 radiologists blinded to the EC-MRI results. A new EC-MRI 1 year later and clinical, analytical, and sonographic follow-up every 6 months for a median of 10 years was performed. Results: A total of 55 non-conclusively benign nodules with APHE were detected at EC-MRI in 41 patients. While 32 of them were suggestive of HCC by EC-MRI, all the 55 nodules showed increased uptake of hepatobiliary contrast. An unequivocal central scar was seen in 12/55 nodules at HB-MRI regardless of it was not detected on the EC-MRI. None of the nodules was hypointense in the hepatobiliary phase (HBP). HCC was not detected during a median of 10 years of follow-up. Conclusions: Detection of nodules with APHE is frequent in patients with BCS, but HCC is rare in Western patients with BCS. While EC-MRI may detect nodules suggesting malignancy, the identification of contrast uptake in the HBP at HB-MRI may help categorize them as benign. [ABSTRACT FROM AUTHOR]

This article discusses the use of [18F]FDG PET/CT imaging in diagnosing infections in cardiac implantable electronic devices (CIEDs). The study highlights the potential for false positive results due to reactive changes and the use of antibacterial envelopes. The case study presented a patient with intense FDG uptake around the device generator, which was later determined to be a reactive response to the antibacterial envelope rather than an infection. This finding suggests that clinicians should consider the possibility of false positive results when interpreting PET/CT scans of CIEDs. [Extracted from the article]

The sympathetic denervation studies and the studies of microvascular involvement are the most important tools for early detection of Chagas heart disease. Especially the 123I-123I-MIBGSPECT or 11C-meta-hydroxyephedrine-PET studies since everything starts from sympathetic denervation. Also it is advisable to insist on the assessment of other parameters of early involvement of left ventricular systolic function to understand the importance of the additional information provided by the analysis of the parameters of ventricular remodeling, synchrony, and GLS in patients with normal left ventricular ejection fraction and in the absence of ventricular dilatation for early detection of myocardial dysfunction. [ABSTRACT FROM AUTHOR]

El objetivo es estudiar la relación entre los parámetros estructurales, de remodelado, de sincronía y de función sistólica del ventrículo izquierdo (VI) mediante gSPECT. Obtener los valores de corte del VI para el índice de la forma telediastólica (iFTD), el índice de la forma telesistólica (iFTS), el índice de excentricidad (iEX) y la velocidad máxima de vaciado (VMV). Desarrollar un nuevo índice para evaluar diferentes patrones de función sistólica del VI. Analizamos prospectivamente 238 pacientes (edad: 63,4 ± 13 años) estudiados mediante gSPECT de esfuerzo-reposo (grupo-control, n = 148; pacientes con infarto de miocardio [IM] previo, n = 90). Estudio aprobado por el Comité de Ética del Hospital (PR[AG]168.2010). En el grupo-control, el índice del volumen telediastólico (iVTD) y el iEX influyeron en el iFTD (r2: 0,52, p < 0,001). El iVTD, la VMV, ser varones y el iEX (r2: 0,44; p < 0,001) influyeron en el iFTS. El iFTD, iFTS, la fracción de eyección VI (FEVI) y el volumen de eyección sistólica (r2: 0,62; p < 0,001) influyeron en el iEX. La FEVI, la frecuencia cardíaca, el ancho de banda (AB) y la desviación estándar influyeron (r2: 0,76; p < 0,001) en la VMV. Los valores de corte para iFTD, iFTS, iEX y VMV fueron 0,59, 0,42, 0,87 y −3,3 respectivamente. La VMV, el iFTS y el AB fueron los parámetros mejor relacionados con los pacientes con IM previo (AUC: 0,89), y sumados a la FEVI permitieron obtener distintos patrones de función sistólica (índice PERRS). Los parámetros de remodelado, sincronía y función sistólica del VI deben interpretarse simultáneamente, ya que esto permite obtener distintos patrones de función sistólica del VI. The aim of this study is to assess the relationship between structural, remodeling, synchrony, and systolic left ventricular (LV) function parameters using gated-SPECT myocardial-perfusion-images (gSPECT-MPI). In addition, obtaining the cut-off values for end-diastolic LV-shape-index (EDLVsi), end-systolic LV-shape-index (ESLVsi), ECC (eccentricity-index) and PER, and developing a new index to evaluate different patterns of the LV systolic function. The study was approved by the Hospital's Ethical-Committee (PR[AG]168.2010), and all patients gave their informed consent. We analyzed prospectively 238 patients (age 63.4 ± 13 years) who underwent stress-rest gSPECT-MPI (control-group, n = 148; patients with previous myocardial infarction [MI], n = 90). In the control group, with regard to remodeling parameters: the end-diastolic-volume-index (EDV) and the ECC were the parameters that influenced the EDLVsi (r 2: 0.52, P <.001). EDV, PER, men, and the ECC were the parameters (r 2: 0.44; P <.001) which influenced the ESLVsi. EDLVsi, ESLVsi, LVEF and the stroke-volume were the parameters (r 2: 0.62; P <.001) which influenced the ECC. With regards to PER: LVEF, heart-rate, bandwidth, and the standard-deviation were the influencing parameters (r 2: 0.76; P <.001). The cut-off values for EDLVsi, ESLVsi, ECC, and PER were 0.59, 0.42, 0.87, and 3.3, respectively. The PER, the ESLVsi and the bandwidth were the parameters related to patients with previous MI (AUC: 0.89); and they allow the assessment of different patterns of systolic function (PERRS-index: Peak-Emptying-Rate, left ventricular-Remodeling and Synchrony). The remodeling, synchrony and the systolic function parameters of the LV should be interpreted together (PERRS-index). In this way, we obtain different patterns of LV systolic function. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with early-stage BCLC 0/A hepatocellular carcinoma (HCC) who are not candidates for liver transplantation or resection are treated with percutaneous ablation according to guidelines. Nevertheless, these patients are at high risk of HCC recurrence and physicians must apply different criteria to choose the salvage treatment as part of the Clinical Decision-Making process. This study analyzed the outcome of 225 BCLC 0/A HCC patients treated with ablation, focusing beyond the classical factors of tumor burden, liver function, and/or performance status. We found that the risk of death is two times higher (HR 2.0) if the comorbidities prevent further sequential locoregional or systemic treatments. The data in this study provide significant and useful prognosis information for physicians and provide valuable information to researchers involved in clinical practice and research by adding granularity to the evolutionary events of HCC patients with recurrence after percutaneous ablation. Background: Ablation is a first-line treatment for Barcelona Clinic Liver Cancer (BCLC)-0/A hepatocellular carcinoma (HCC). However, there are scarce data about patients' outcomes after recurrence. The present study evaluates the impact of patient and tumor characteristics at baseline and at recurrence on the Clinical Decision-Making process. Methods: We evaluated BCLC-0/A patients treated with percutaneous ablation from January 2010 to November 2018. Clinical and radiological data such as age, tumor location at ablation, pattern of recurrence/progression, and comorbidities during follow-up were registered. Tumor location was divided into 'suboptimal' vs. 'optimal' locations for ablation. The Clinical Decision-Making was based on tumor burden, liver dysfunction, or comorbidities. The statistical analysis included the time-to-recurrence/progression, censoring at time of death, date of last follow-up or liver transplantation, and time-to-event was estimated by the Kaplan–Meier method and Cox regression models to evaluate the risk of an event of death and change of treatment strategy. Results: A total of 225 patients [39.1% BCLC-0 and 60.9% BCLC-A] were included, 190 had unifocal HCC and 82.6% were ≤3 cm. The complete response rate and median overall survival were 96% and 60.7 months. The HCC nodules number (Hazard Ratio—HR 3.1), Child-Pugh (HR 2.4), and Albumin-Bilirubin score (HR 3.2) were associated with increased risk of death during follow-up. HCC in 'suboptimal location' presented a shorter time to recurrence. When comorbidities prevented further loco-regional or systemic treatment, the risk of death was significantly increased (HR 2.0, p = 0.0369) in comparison to those who received treatment. Conclusions: These results expose the impact of non-liver comorbidities when considering treatment for recurrence after ablation in the real-world setting and in research trials. Ultimately, we identified an orphan population for which effective interventions are needed. [ABSTRACT FROM AUTHOR]

Los radiotrazadores con afinidad ósea como el [99mTc]Tc-DPD han demostrado una alta sensibilidad y especificidad en el diagnóstico no invasivo de la amiloidosis cardíaca (AC) por transtirretina (ATTR-AC). Este estudio tiene como objetivo validar el uso de la SPECT/TC y evaluar la utilidad de la cuantificación de la captación (cargaDPD) en el tejido miocárdico como información potencial sobre la carga amiloide. Se trata de un análisis retrospectivo de 46 pacientes con sospecha de AC, en el que 23 casos con ATTR-AC fueron sometidos a dos métodos de cuantificación para estimar la carga amiloide (cargaDPD) a través de imágenes planares y de una SPECT/TC. La SPECT/TC aportó un valor añadido significativo en el diagnóstico del paciente con AC (p < 0,05). La estimación de la carga amiloide comprobó que la pared del VI más afectada es el tabique interventricular en la mayoría de los casos, y la existencia de una relación significativa entre la captación de Perugini y la carga de DPD. Validamos la necesidad de la SPECT/TC como complemento de la imagen planar en el diagnóstico de la AC-TTR. Por su parte, el cálculo de la carga amiloide continúa siendo un área de investigación compleja y requiere de más estudios, con un mayor número de pacientes, que permitan validar un método estandarizado de cuantificación de la carga de amiloide, tanto para el diagnóstico como para el seguimiento del tratamiento. Bone tracers such as [99mTc]Tc-DPD have shown high sensitivity and specificity in the non-invasive diagnosis of transthyretin cardiac amyloidosis (ATTR-AC). This study aims to validate SPECT/CT and assess the usefulness of uptake quantification (burdenDPD) in the myocardial tissue as potential information on the amyloid burden. In a retrospective analysis of 46 patients with suspected CA, 23 cases with ATTR-AC had two quantification methods conducted to estimate amyloid burden (burdenDPD) through planar scintigraphic scans and a SPECT/CT. SPECT/CT significantly provided an added value in the patient's diagnosis with CA (P <.05). The estimation of the amyloid burden substantiated that the most affected wall of the LV is the interventricular septum in most cases and the existence of a significant relationship between the Perugini score uptake and the burdenDPD. We validate the need for SPECT/CT to complement planar imaging in diagnosing ATTR-AC. For its part, quantifying the amyloid load continues to be a complex area of research. It requires further studies with a larger number of patients to validate a standardized method of amyloid load quantification, both for diagnosis and treatment monitoring. [ABSTRACT FROM AUTHOR]

Background: To evaluate the Vall d'Hebron-Risk-Score (VH-RS) to stratify the risk of patients with stable ischemic cardiomyopathy (ICM), and assess whether hemoglobin (Hb) and estimated glomerular filtration rate (eGFR) provide additional information to the VH-RS. Methods and results: We analysed 673 consecutive patients with ICM who underwent gated SPECT. According to VH-RS, we stratified patients into 4-risk-levels: very-low-risk (VLR), low-risk (LR), moderate-risk (MR), and high-risk (HRi). We considered as MACEs: non-fatal myocardial infarction (MI), heart failure hospitalization (HF), coronary revascularization (CR), and cardiac death (CD). Also the cardiac-resynchronization-therapy (CRT), and the implantable-cardioverter-defibrillator (ICD) were investigated. During the follow-up (4.8 ± 2.7 years), 379 patients had MACEs (0.18/patient/year). There were no patients in VLR and LR. All patients were reclassified in 3-risk-levels (MRi = 48; HRi = 121; VHRi[very high risk] = 504). Most patients with MACEs were in VHRi level (test-for-trend: MACEs ≥ 1 without CRT/ICD, P <.001; combined non-fatal MI, CD and CR, P <.001; MACEs ≥ 1 with CRT/ICD, P <.001). The Hb and eGFR values do not properly improve the risk stratification obtained by the VH-RS (global-NRI[net-reclassification-improvement] was: (MACEs ≥ 1 without CRT/ICD: − 10.6%; non-fatal MI, CD and CR: − 9.08%; and MACEs ≥ 1 with CRT/ICD: − 8.85%). Conclusion: VH-RS is effective in evaluating risk of patients with stable ICM. In our population, adding Hb and eGFR variables do not improve the performance of the VH-RS. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate survival, efficacy and safety of transarterial chemoembolization (TACE) in the treatment of patients with hepatocellular carcinoma (HCC), through a pooled analysis of patients with BCLC 0, A and B HCC stages, treated with polyethylene glycol drug eluting microspheres (PEG-DEM) TACE. Materials and Methods: Patients from 3 retrospective and 2 prospective registries were included. Overall survival (OS), progression-free survival (PFS), tumour response and safety were evaluated. Multivariate Cox regression analysis was performed to evaluate predictors of OS. Results: A total of 580 patients (72.1% males, mean age 66.9 ± 10.3 years) were included. 43.5% had BCLC A, and 41.0% BCLC B disease stage, and 85.8% were Child–Pugh class A. Complete and partial response (mRECIST or RECIST1.1) were achieved in 60.14% and 27.11% of patients, with overall response and disease control rates of 87.30% and 94.60%, respectively. Median OS was 50.8 months for the total population, and 61.2 and 38.1 months for BCLC 0 + A and BCLC B patients, respectively. Median PFS for the total population, BCLC 0 + A and BCLC B groups was 15.6, 21.6 and 12.7 months, respectively. Conclusions: This multicentric pooled analysis confirmed efficacy and safety of PEG-DEM TACE, with a median OS of 50.8 months. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is responsible for high incidence of cardiovascular (CV) complications leading to heart failure. Coronary artery region-specific metabolic and structural assessment could provide deeper insight into the extent of the disease and help prevent adverse cardiac events. Therefore, in this study, we aimed at investigating such myocardial dynamics for the first time in insulin-sensitive (mIS) and insulin-resistant (mIR) T2D patients. We targeted global and region-specific variations using insulin sensitivity (IS) and coronary artery calcifications (CACs) as CV risk factor in T2D patients. IS was computed using myocardial segmentation approaches at both baseline and after an hyperglycemic–insulinemic clamp (HEC) on [18F]FDG-PET images using the standardized uptake value (SUV) (ΔSUV = SUVHEC − SUVBASELINE) and calcifications using CT Calcium Scoring. Results suggest that some communicating pathways between response to insulin and calcification are present in the myocardium, whilst differences between coronary arteries were only observed in the mIS cohort. Risk indicators were mostly observed for mIR and highly calcified subjects, which supports previously stated findings that exhibit a distinguished exposure depending on the impairment of response to insulin, while projecting added potential complications due to arterial obstruction. Moreover, a pattern relating calcification and T2D phenotypes was observed suggesting the avoidance of insulin treatment in mIS but its endorsement in mIR subjects. The right coronary artery displayed more ΔSUV, whilst plaque was more present in the circumflex. However, differences between phenotypes, and therefore CV risk, were associated to left descending artery (LAD) translating into higher CACs regarding IR, which could explain why insulin treatment was effective for LAD at the expense of higher likelihood of plaque accumulation. Personalized approaches to assess T2D may lead to more efficient treatments and risk-prevention strategies. [ABSTRACT FROM AUTHOR]

We present a method for accelerating the global structure optimization of atomic compounds. The method is demonstrated to speed up the finding of the anatase TiO2(001)-(1 × 4) surface reconstruction within a density functional tight-binding theory framework using an evolutionary algorithm. As a key element of the method, we use unsupervised machine learning techniques to categorize atoms present in a diverse set of partially disordered surface structures into clusters of atoms having similar local atomic environments. Analysis of more than 1000 different structures shows that the total energy of the structures correlates with the summed distances of the atomic environments to their respective cluster centers in feature space, where the sum runs over all atoms in each structure. Our method is formulated as a gradient based minimization of this summed cluster distance for a given structure and alternates with a standard gradient based energy minimization. While the latter minimization ensures local relaxation within a given energy basin, the former enables escapes from meta-stable basins and hence increases the overall performance of the global optimization. [ABSTRACT FROM AUTHOR]

Aims The burden of ischaemia is a risk factor for adverse outcomes in ischaemic cardiomyopathy (ICM) but is not systematically tested when deciding on revascularization. Limited data exists in patients with ICM regarding the interaction between ischaemia and early coronary revascularization (ECR). This study sought to determine if the burden of ischaemia modifies the outcomes of ECR in ICM. Methods and results Consecutive patients with ICM (left ventricular ejection fraction < 40%) with a stress-rest gated single-photon emission computed tomography (N  = 747) were followed-up for ECR and major cardiovascular events (MACEs, cardiovascular death, myocardial infarction, or heart failure hospitalization). A 1:1 matched population was selected using a propensity score for ECR. The interaction between ischaemia and ECR was evaluated in the matched cohort. In the initial cohort, 131 patients underwent ECR. Of them, 109 were matched to non-ECR patients. After a median follow up of 4.1 years, 102 (46.8%) patients experienced a MACE. The effect of revascularization on MACE was dependent of the percent of ischaemia (P for the interaction at 10% ischaemia = 0.021), so that a trend towards a decreased risk of MACE was seen in patients with >10% of ischaemia [hazard ratio (HR) = 0.59 (0.30–1.18)], whereas a non-significant increase of MACE was observed in those with <10% ischaemia (HR = 1.67 [0.94–2.96]). Conclusions In a contemporary cohort of patients with ICM, the beneficial effects of ECR may be mediated by the percent of ischaemia. This study supports stress testing in ICM and an ischaemia-guided approach for ECR. [ABSTRACT FROM AUTHOR]

Background: Sorafenib constitutes a suitable treatment alternative for patients with advanced hepatocellular carcinoma (HCC) in whom atezolizumab + bevacizumab therapy is contraindicated. The aim of the study was the identification of a miRNA signature in liquid biopsy related to sorafenib response. Methods: miRNAs were profiled in hepatoblastoma HepG2 cells and tested in animal models, extracellular vesicles (EVs), and plasma from HCC patients. Results: Sorafenib altered the expression of 11 miRNAs in HepG2 cells. miR-200c-3p and miR-27a-3p exerted an anti-tumoral activity by decreasing cell migration and invasion, whereas miR-122-5p, miR-148b-3p, miR-194-5p, miR-222-5p, and miR-512-3p exerted pro-tumoral properties by increasing cell proliferation, migration, or invasion, or decreasing apoptosis. Sorafenib induced a change in EVs population with an increased number of larger EVs, and promoted an accumulation of miR-27a-3p, miR-122-5p, miR-148b-3p, miR-193b-3p, miR-194-5p, miR-200c-3p, and miR-375 into exosomes. In HCC patients, circulating miR-200c-3p baseline levels were associated with increased survival, whereas high levels of miR-222-5p and miR-512-3p after 1 month of sorafenib treatment were related to poor prognosis. The RNA sequencing revealed that miR-200c-3p was related to the regulation of cell growth and death, whereas miR-222-5p and miR-512-3p were related to metabolic control. Conclusions: The study showed that Sorafenib regulates a specific miRNA signature in which miR-200c-3p, miR-222-5p, and miR-512-3p bear prognostic value and contribute to treatment response. [ABSTRACT FROM AUTHOR]

Aims Diagnosis of prosthetic valve endocarditis (PVE) by positron emission computed tomography angiography (PET/CTA) is based on visual and quantitative morpho-metabolic features. However, the fluorodeoxyglucose (FDG) uptake pattern can be sometimes visually unclear and susceptible to subjectivity. This study aimed to validate a new parameter, the valve uptake index [VUI, maximum standardized uptake value (SUVmax)−mean standardized uptake value (SUVmean)/SUVmax], designed to provide a more objective indication of the distribution of metabolic activity. Secondly, to re-evaluate the utility of traditionally used PVE imaging criteria and determine the potential value of adding the VUI in the diagnostic algorithm of PVE. Methods and results Retrospective analysis of 122 patients (135 prosthetic valves) admitted for suspicion of endocarditis, with a conclusive diagnosis of definite (N = 57) or rejected (N = 65) PVE, and who had undergone a cardiac PET/CTA scan as part of the diagnostic evaluation. We measured the VUI and recorded the SUVmax, SUVratio, uptake pattern, and the presence of endocarditis-related anatomic lesions. The VUI, SUVmax, and SUVratio values were 0.54 ± 0.1 vs. 0.36 ± 0.08, 7.68 ± 3.07 vs. 3.72 ± 1.11, and 4.28 ± 1.93 vs. 2.16 ± 0.95 in the 'definite' PVE group vs. the 'rejected' group, respectively (mean ± SD; P < 0.001). A cut-off value of VUI > 0.45 showed a sensitivity, specificity, and diagnostic accuracy for PVE of 85%, 88%, and 86.7% and increased diagnostic ability for confirming endocarditis when combined with the standard diagnostic criteria. Conclusions The VUI demonstrated good diagnostic accuracy for PVE, even increasing the diagnostic power of the traditionally used morphometabolic parameters, which also confirmed their own diagnostic performance. More research is needed to assess whether the integration of the VUI into the PVE diagnostic algorithm may clarify doubtful cases and thus improve the diagnostic yield of PET/CTA. [ABSTRACT FROM AUTHOR]

The aim of the study was to analyze the association between the liver uptake of Gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-EOB-DTPA) in the hepatobiliary phase (HBP) in cirrhotic patients and the presence of clinically significant portal hypertension (CSPH), and how these features impact on hepatocellular carcinoma (HCC) detection in the HBP. Post-hoc analysis of a prospective cohort of 62 cirrhotic patients with newly US-detected nodule between 1–2 cm (study group). Twenty healthy subjects were used as control group. Qualitative and quantitative analysis of the liver contrast uptake in the HBP assessed by Relative Liver-Enhancement (RLE), Liver-Spleen (LSCR), Liver-Muscle (LMCR), and Liver-Kidney Contrast-Ratio (LKCR), Contrast Enhancement Index (CEI), and Hepatic Uptake (HUI), and biliary excretion, were registered. CSPH was confirmed invasively (HVPG > 10 mmHg) or by indirect parameters. The appearance of HCC at the HBP was analyzed. Nineteen patients (30.6%) did not have CSPH. In 41 patients (66.1%) the final diagnosis was HCC. All indices were significantly higher in the control group, indicating a more intense HBP liver signal intensity compared to patients with cirrhosis, even if the comparison was restricted to patients with no CSPH. CSPH was associated to a lower rate of HCC hypointensity in the HBP (51.9% vs. 85.7% without CSPH, p = 0.004). Liver uptake of Gd-EOB-DTPA at the HBP is decreased in cirrhosis even if the liver function is minimally impaired and it falls down significantly in patients with CSPH compromising the recognition of hypointense lesions. This fact may represent a limitation for the detection of small HCC in patients with cirrhosis and CSPH. [ABSTRACT FROM AUTHOR]

Gastrointestinal adverse events (GIAEs) are common in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. Diarrhea is a prevalent event responsible for treatment interruptions and dosage modifications. Our study evaluates the role of baseline blood L-glutamine (L-Gln) levels in the prediction of gastrointestinal adverse events development early during treatment (eGIAE). Blood L-Gln was measured in 135 patients with advanced HCC prior to starting sorafenib. Any adverse events developed during therapy were registered in a prospective database. We used Mann–Whitney U and Fisher's exact tests to compare quantitative or categorical variables, respectively, Kaplan–Meier method to analyze time to event variables, log-rank test for the survival functions and Cox regression models to estimate hazard ratios (HR). Fifteen per cent of patients developed eGIAE, with diarrhea as the most frequent one. Patients displaying the lowest L-Gln levels presented a significant higher risk of eGIAE, while those with the highest levels were protected from eGIAE and achieved better survival. Our study shows for the first time the association of baseline blood L-Gln levels with eGIAE development in HCC patients during sorafenib treatment. Low L-Gln concentrations might reflect a potentially compromised intestinal barrier that becomes clinically relevant early after treatment start. [ABSTRACT FROM AUTHOR]

Background: We report that myocardial insulin resistance (mIR) occurs in around 60% of patients with type 2 diabetes (T2D) and was associated with higher cardiovascular risk in comparison with patients with insulin-sensitive myocardium (mIS). These two phenotypes (mIR vs. mIS) can only be assessed using time-consuming and expensive methods. The aim of the present study is to search a simple and reliable surrogate to identify both phenotypes. Methods: Forty-seven patients with T2D underwent myocardial [18F]FDG PET/CT at baseline and after a hyperinsulinemic–euglycemic clamp (HEC) to determine mIR were prospectively recruited. Biochemical assessments were performed before and after the HEC. Baseline hepatic steatosis index and index of hepatic fibrosis (FIB-4) were calculated. Furthermore, liver stiffness measurement was performed using transient elastography. Results: The best model to predict the presence of mIR was the combination of transaminases, protein levels, FIB-4 score and HOMA (AUC = 0.95; sensibility: 0.81; specificity: 0.95). We observed significantly higher levels of fibrosis in patients with mIR than in those with mIS (p = 0.034). In addition, we found that patients with mIR presented a reduced glucose uptake by the liver in comparison with patients with mIS. Conclusions: The combination of HOMA, protein, transaminases and FIB-4 is a simple and reliable tool for identifying mIR in patients with T2D. This information will be useful to improve the stratification of cardiovascular risk in T2D. [ABSTRACT FROM AUTHOR]

Background & Aims: Information about the impact of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) in patients with liver cancer is lacking. This study characterizes the outcomes and mortality risk in this population. Methods: Multicentre retrospective, cross‐sectional, international study of liver cancer patients with SARS‐CoV‐2 infection registered between February and December 2020. Clinical data at SARS‐CoV‐2 diagnosis and outcomes were registered. Results: Two hundred fifty patients from 38 centres were included, 218 with hepatocellular carcinoma (HCC) and 32 with intrahepatic cholangiocarcinoma (iCCA). The median age was 66.5 and 64.5 years, and 84.9% and 21.9% had cirrhosis in the HCC and iCCA cohorts respectively. Patients had advanced cancer stage at SARS‐CoV‐2 diagnosis in 39.0% of the HCC and 71.9% of the iCCA patients. After a median follow‐up of 7.20 (IQR: 1.84–11.24) months, 100 (40%) patients have died, 48% of the deaths were SARS‐CoV‐2‐related. Forty (18.4%) HCC patients died within 30‐days. The death rate increase was significantly different according to the BCLC stage (6.10% [95% CI 2.24–12.74], 11.76% [95% CI 4.73–22.30], 20.69% [95% CI 11.35–31.96] and 34.52% [95% CI 17.03–52.78] for BCLC 0/A, B, C and D, respectively; p =.0017). The hazard ratio was 1.45 (95% CI 0.49–4.31; p =.5032) in BCLC‐B versus 0/A, and 3.13 (95% CI 1.29–7.62; p =.0118) in BCLC‐C versus 0/A in the competing risk Cox regression model. Nineteen out of 32 iCCA (59.4%) died, and 12 deaths were related to SARS‐CoV‐2 infection. Conclusions: This is the largest cohort of liver cancer patients infected with SARS‐CoV‐2. It characterizes the 30‐day mortality risk of SARS‐CoV‐2 infected patients with HCC during this period. [ABSTRACT FROM AUTHOR]

La captación miocárdica en la gammagrafía ósea se ha convertido en un método útil para la detección de la amiloidosis cardiaca secundaria al depósito de transtirretina (ATTR-CA). El objetivo de este estudio fue evaluar la prevalencia de captación miocárdica en pacientes mayores de 18 años sin sospecha clínica de amiloidosis cardiaca (AC) y a los que se realizó una gammagrafía ósea. Se trata de un estudio observacional, retrospectivo y multicéntrico realizado en 21 hospitales de España (de septiembre a noviembre de 2019). De las 9.864 gammagrafías analizadas (de forma local y central), en 71 pacientes (0,72%), se observó captación cardiaca incidental, con una prevalencia que aumentó con la edad. En el 16,9% de los pacientes con captación positiva se detectó un diagnóstico previo de insuficiencia cardiaca (IC), con > 50% de los pacientes en un grado II de la clasificación de la NYHA. En 10 pacientes se realizó el diagnóstico de ATTR-CA, con un retraso medio de 10,4 meses (IC 95%: 5,1-15,7). Todos ellos eran mayores de 70 años, principalmente varones y presentaban una mayor hipertrofia ventricular izquierda (HVI) respecto a los pacientes sin diagnóstico confirmado (p < 0,0001). Los pacientes con ATTR-CA presentaron una mayor tasa de hipotensión ortostática (30,0% vs. 3,8% en los pacientes sin ATTR-CA; p = 0,025). Se trata del primer estudio retrospectivo, de ámbito nacional y multicéntrico que evalúa la prevalencia de captación cardiaca incidental en gammagrafías óseas realizadas por motivos extracardiacos, y que muestra una prevalencia del 0,72% en esta población. La derivación de estos pacientes puede facilitar el diagnóstico precoz de la AC con el consiguiente beneficio para los mismos. Myocardial uptake on bone scintigraphy has become useful for the detection of transthyretin cardiac amyloidosis (ATTR-CA). This study aimed to assess the prevalence of myocardial uptake in patients over 18 years of age with no clinical suspicion of cardiac amyloidosis (CA) who had undergone bone scintigraphy. This was an observational, retrospective, multicenter study across 21 Spanish hospitals (September–November 2019). Of the 9864 scans analyzed (locally and centrally), incidental cardiac uptake was observed in 71 patients (0.72%), a prevalence that increased with age. A previous diagnosis of heart failure was found in 16.9% of patients with positive uptake, with >50% in NYHA II. ATTR-CA was diagnosed in 10 patients, with a mean delay of 10.4 months (95% CI: 5.1-15.7). All were >70 years old, primarily male, and had greater left ventricular hypertrophy than patients without a confirmed diagnosis (p < 0.0001). ATTR-CA patients had higher rates of orthostatic hypotension (30.0% vs. 3.8% in non-ATTR-CA; p = 0.025). This is the first retrospective, national, multicenter study evaluating the prevalence of incidental cardiac uptake in bone scintigraphy performed for non-cardiac reasons, showing a prevalence of 0.72% in this population. Referral of these patients may facilitate early diagnosis of CA with a resulting benefit for patients. [ABSTRACT FROM AUTHOR]

Background and Aims: PTTG1 is almost undetectable in adult livers but is highly expressed in hepatocarcinoma. While little is known about its involvement in liver fibrosis, PTTG1 expression is associated with DLK1. We assessed the role of the PTTG1/DLK1 pathway in fibrosis progression and the potential therapeutic effect of PTTG1 silencing in fibrosis. Methods: Pttg1 and Dlk1 were studied in liver and isolated cell populations of control and fibrotic rats and in human liver biopsies. The fibrotic molecular signature was analysed in Pttg1−/− and Pttg1+/+ fibrotic mice. Finally, Pttg1 silencing was evaluated in rats as a novel antifibrotic therapy. Results: Pttg1 and Dlk1 mRNA selectively increased in fibrotic rats paralleling fibrosis progression. Serum DLK1 concentrations correlated with hepatic collagen content and systemic and portal haemodynamics. Human cirrhotic livers showed greater PTTG1 and DLK1 transcript abundance than non‐cirrhotic, and reduced collagen was observed in Pttg1Pttg1−/− mice. The liver fibrotic molecular signature revealed lower expression of genes related to extracellular matrix remodelling including Mmp8 and 9 and Timp4 and greater eotaxin and Mmp13 than fibrotic Pttg1+/+ mice. Finally, interfering Pttg1 resulted in reduced liver fibrotic area, lower α‐Sma and decreased portal pressure than fibrotic animals. Furthermore, Pttg1 silencing decreased the transcription of Dlk1, collagens I and III, Pdgfrβ, Tgfrβ, Timp1, Timp2 and Mmp2. Conclusions: Pttg1/Dlk1 are selectively overexpressed in the cirrhotic liver and participate in ECM turnover regulation. Pttg1 disruption decreases Dlk1 transcription and attenuates collagen deposition. PTTG1/DLK1 signalling is a novel pathway for targeting the progression of liver fibrosis. [ABSTRACT FROM AUTHOR]

18F-FDG-PET/CT, especially when performed in combination with cardiac CT angiography (PET/CTA), has shown a significant improvement in the diagnostic yield of prosthetic valve endocarditis (PVE).[1] Abnormal metabolic activity associated to a prosthetic heart valve (PHV) has become a major criterion in the 2015 European Society of Cardiology diagnostic criteria for PVE. To complete patient evaluation, a cardiac PET/CTA was performed, and depicted diffuse and homogeneous intense FDG uptake with no associated anatomic lesions (Figure 1), findings that were interpreted as low suggestive for infection based on our previous experience.[3] Nevertheless, given the absence of an alternative infectious focus, it was decided to treat it as a I possible i PVE. Fused PET/CTA transverse views of the aortic valve (upper row) showed stability of the metabolic activity intensity (initial SUVmax 6.5 vs. 6.7 at follow-up) and no changes in the distribution pattern, diffuse and homogeneous in both the studies. [Extracted from the article]

Background: Diabetes mellitus is an independent risk factor in the development of coronary artery disease (CAD), myocardial infarction (MI), and cardiac death (CD). The major adverse cardiac events (MACEs) between men and women in diabetic patients stratified by CAD (previous MI and/or coronary revascularization, CR) were analyzed. Methods and Results: A cohort of 1327 consecutive diabetic patients (age 66.5 ± 9 years) underwent gated SPECT (single-photon emission computed tomography). During a mean follow-up of 4.7 ± 2.2 years post gated SPECT, MACEs (non-fatal MI, CD, and late CR) were evaluated according to gender stratified by CAD. Among diabetic patients without known CAD (N = 731), men had more MACEs (sHR 1.9;95%CI 1.2-3.2) than women. Among diabetic patients with known CAD (N = 596), there was no difference in MACEs in diabetic men and women (sHR 1.15;95%CI 0.73-1.8). Diabetic women with known CAD (n = 143) were the group with the highest risk (sHR 1.7; P =.041) for MACEs (4.5% MACEs/year, [95%CI 3.1%-6.4%]), compared to the remaining diabetic patients (N = 1184) (3% MACEs/year, [95%CI 2.6%-3.5%]). Conclusions: The prognosis of diabetic patients for MACEs is different in men and women stratified by CAD. The worst prognosis for MACEs occurs in women with known CAD. [ABSTRACT FROM AUTHOR]

The American College of Radiology has released the Liver Imaging Reporting and Data System (LI-RADS) scheme which categorizes focal liver lesions (FLLs) in patients at risk for hepatocellular carcinoma (HCC) according to the degree of risk of nodules to be HCC. It subgroups FLL in LR-1 (definitely benign), LR-2 (probably benign), LR-3 (intermediate probability of malignancy), LR-4 (probably HCC), LR-5 (definitely HCC), and LR-M (probable malignancy not specific for HCC). Computed tomography/magnetic resonance imaging (CT/MRI) and contrast enhanced ultrasound (CEUS) LI-RADS diagnostic algorithm have the goal to standardize the acquisition, interpretation, reporting, and data collection for imaging examinations in patients at risk for HCC. Nevertheless, there remain controversial issues that should be dealt with. The aim of this review is to discuss the pros and cons of the interpretation and reporting part of CT/MRI and CEUS LI-RADS diagnostic algorithm to permit future refinements of the scheme and optimize patient and nodule management. [ABSTRACT FROM AUTHOR]

Introduction: Atezolizumab (ATEZO) plus bevacizumab (BEVA) represents the new standard of care for the treatment of advanced hepatocellular carcinoma (HCC). However, the choice of the second-line treatment after the failure of immunotherapy-based first-line remains elusive. Taking into account the weaknesses of the available evidence, we developed a simulation model based on available phase III randomized clinical trials (RCTs) to identify optimal risk/benefit sequential strategies. Methods: A Markov model was built to estimate the overall survival (OS) of sequential first- and second-line systemic treatments. Sequences starting with first-line ATEZO plus BEVA followed by 5 second-line treatments (sorafenib [SORA], lenvatinib [LENVA], regorafenib, cabozantinib, and ramucirumab) were compared. The probability of transition between states (initial treatment, cancer progression, and death) was derived from RCTs. Life-year gained (LYG) was the main outcome. Rates of severe adverse events (SAEs) (≥ grade 3) were calculated. The incremental safety-effectiveness ratio (ISER) was calculated as the difference in probability of SAEs divided by LYG between the 2 most effective sequences. Results: ATEZO plus BEVA followed by LENVA (median OS, 24 months) or SORA (median OS, 23 months) was the most effective sequence, producing a LYG of 0.50 and 0.42 year, respectively. ATEZO plus BEVA followed by SORA was the safest sequence (SAEs 63%). At a willingness-to-risk threshold of 10% of SAEs for LYG, ATEZO plus BEVA followed by second-line SORA was favored in 72% of cases, while at a threshold of 30% of SAEs for LYG, ATEZO plus BEVA followed by second-line LENVA was favored in 69% of cases. Conclusion: Our simulation model provides a strong rationale to support ongoing trials evaluating second-line tyrosine-kinase inhibitors after first-line ATEZO plus BEVA. Future evidence from ongoing RCTs and prospective real-world studies are needed to prove the net health benefit of sequential treatment options for advanced HCC. [ABSTRACT FROM AUTHOR]

Purpose: The efficacy and safety of regorafenib have been demonstrated in phase 3 trials for multiple tumor types, including metastatic colorectal cancer (mCRC) (CORRECT [NCT01103323]; CONCUR [NCT01584830]), advanced gastrointestinal stromal tumor (GIST) (GRID [NCT01271712]), and hepatocellular carcinoma (HCC) (RESORCE [NCT01774344]). The objective of this post hoc exploratory analysis was to explore the impact of regorafenib on delaying health-related quality of life (HRQOL) deterioration across these tumor types. Patients and Methods: HRQOL data (assessed with EORTC QLQ-C30 and EQ-5D questionnaires) were pooled for all trials to determine time until definitive deterioration (TUDD), defined as the patient's first minimal clinically important deterioration in HRQOL score from baseline that does not resolve, using stratified Kaplan–Meier estimators and Cox proportional hazards models adjusted for relevant trial, cancer type, and baseline covariates. Additional analyses based on cancer type were conducted by pooling mCRC trials (CORRECT and CONCUR) and pooling the two mCRC trials with the HCC trial (RESORCE). Results: A total of 1699 patients with HRQOL data were pooled across the four trials. The results showed that regorafenib significantly delayed TUDD compared with placebo across all three tumor types. Median time to deterioration across the five scales ranged from 16.3 to 24.1 weeks for regorafenib and 8.6 to 12.1 weeks for placebo. The results from the individual studies, the pooled mCRC trials, and the pooled mCRC and HCC trials were similar to the overall pooled results. Conclusion: A pooled analysis of four phase 3 trials demonstrated that regorafenib delayed a clinically relevant exploratory endpoint, defined as TUDD, compared with placebo across three different tumor types (mCRC, GIST, and HCC), which supports a novel benefit of the impact of regorafenib with respect to patients with these three types of cancers by allowing initial declines in HRQOL to resolve and patients the opportunity to continue treatment. [ABSTRACT FROM AUTHOR]

Objectives: Liver Imaging Reporting and Data System (LI-RADS) for hepatocellular carcinoma (HCC) diagnosis in high-risk patients is a dynamic system, which was lastly updated in 2018. We aimed to evaluate the accuracy for HCC diagnosis of LI-RADS v2018 with magnetic resonance imaging (MRI) with extracellular contrast for solitary nodules ≤ 20 mm detected during ultrasound (US) surveillance in cirrhotic patients, with particular interest in those observations categorized as LI-RADS 3. Methods: Between November 2003 and February 2017, we included 262 consecutive cirrhotic patients with a newly US-detected solitary ≤ 20-mm nodule. A LI-RADS (LR) v2018 category was retrospectively assigned. The diagnostic accuracy for each LR category was described, and the main MRI findings associated with HCC diagnosis were analyzed. Results: Final diagnoses were as follows: 197 HCC (75.2%), 5 cholangiocarcinoma (1.9%), 2 metastasis (0.8%), and 58 benign lesions (22.1%); 0/15 (0%) LR-1, 6/26 (23.1%) LR-2, 51/74 (68.9%) LR-3, 11/12 (91.7%) LR-4, 126/127 (99.2%) LR-5, and 3/8 (37.5%) LR-M were HCC. LR-5 category displayed a sensitivity and specificity of 64% (95% CI, 56.8–70.7) and 98.5% (95% CI, 91.7–100), respectively. Considering also LR-4 as diagnostic for HCC, the sensitivity slightly increased to 69.5% (95% CI, 62.6–75.9) with minor impact on specificity (96.2%; 95% CI, 89.3–99.6). Regarding LR-3 observations, 51 out of 74 were HCC, 2 were non-HCC malignancies, and 20 out of 21 LR-3 nodules > 15 mm (95.2%) were finally categorized as HCC. Conclusions: The high probability of HCC in US-detected LR-3 observations (68.9%) justifies triggering an active diagnostic work-up if intended to diagnose HCC at a very early stage. Key Points: • In cirrhotic patients with nodules ≤ 20 mm detected during US surveillance, 51 out of 74 (68.9%) of LR-3 nodules by MRI corresponded to an HCC. • In LR-3 nodules, HCC diagnosis was closely related to baseline tumor size. All 5 nodules smaller than 1 cm were diagnosed as benign. Oppositely, 20 out of 21 LR-3 observations > 15 mm (95.2%) were diagnosed as HCC. • The high probability of HCC in US-detected LR-3 observations justifies triggering an active diagnostic work-up if intended to diagnose HCC at a very early stage. [ABSTRACT FROM AUTHOR]

Q waves may be observed in the absence of non-viable tissue. However, their scintigraphic translation in patients with ischemic cardiomyopathy (ICM) has not been properly assessed. This study sought to establish the determinants of Q waves in the absence of non-viable tissue and the diagnostic accuracy in this population. A retrospective study enrolling 487 consecutive patients (67.0 [57.4 – 75.4] years), with ICM, LVEF < 40% and narrow QRS who underwent stress-rest 99 m-Tc SPECT was conducted. A 17-segment model for myocardium was used: Myocardium was divided in basal (1 to 6), mid (7 to 12), apical (13 to 16) and apex (17) segments. Non-viable tissue was defined as a severe perfusion defect without systolic thickening. Patients with Q waves (65.7%) had more non-viable tissue, more extensive scar and less ischemia. Q waves had a moderate correlation with non-viable tissue (AUC = 0.63) and were associated with the extension of the scar. After excluding patients with non-viable tissue in any myocardial segment, Q waves were observed in 51.9% of the patients, of which 78.1% had a scar fulfilling viability criteria. The presence of Q waves was associated with the location of these scars in a base-to-apex axis (OR = 1.88 [1.35–2.62] for segment towards the apex) and their extent (OR = 1.19 [1.05 – 1.35] for each segment). In patients with ICM, Q waves discriminate poorly viable from non-viable tissue. Q waves in this population may be due to extensive scars fulfilling viability criteria located in apical segments. [ABSTRACT FROM AUTHOR]

Background: Amyloids are ordered, insoluble protein aggregates, characterized by a cross-ß sheet quaternary structure in which molecules in a ß-strand conformation are stacked along the filament axis via intermolecular interactions. While amyloids are typically associated with pathological conditions, functional amyloids have also been identified and are present in a wide variety of organisms ranging from bacteria to humans. The cytoplasmic polyadenylation element-binding (CPEB) prion-like protein is an mRNA-binding translation regulator, whose neuronal isoforms undergo activity-dependent aggregation, a process that has emerged as a plausible biochemical substrate for memory maintenance. CPEB aggregation is driven by prion-like domains (PLD) that are divergent in sequence across species, and it remains unknown whether such divergent PLDs follow a similar aggregating assembly pathway. Here, we describe the amyloid-like features of the neuronal Aplysia CPEB (ApCPEB) PLD and compare them to those of the Drosophila ortholog, Orb2 PLD. Results: Using in vitro single-molecule and bulk biophysical methods, we find transient oligomers and mature amyloid-like filaments that suggest similarities in the late stages of the assembly pathway for both ApCPEB and Orb2 PLDs. However, while prior to aggregation the Orb2 PLD monomer remains mainly as a random coil in solution, ApCPEB PLD adopts a diversity of conformations comprising a-helical structures that evolve to coiled-coil species, indicating structural differences at the beginning of their amyloid assembly pathways. Conclusion: Our results indicate that divergent PLDs of CPEB proteins from different species retain the ability to form a generic amyloid-like fold through different assembly mechanisms. [ABSTRACT FROM AUTHOR]

Ninety-two percent of patients with criteria for cardiac resynchronization therapy have 3 or 4 abnormal parameters in the phase analysis.[20] If we think about ventricular mechanical resynchronization, we cannot forget the right ventricle (RV) (Figure 1-4th). 10.1007/s12350-017-1036-3. 29071669 29 Moreira RI, Abreu A, Portugal G, Oliveira L, Oliveira M, Rodrigues I. Prognostic effect and modulation of cardiac sympathetic function in heart failure patients treated with cardiac resynchronization therapy. Value of intraventricular dyssynchrony assessment by gated-SPECT myocardial perfusion imaging in the management of heart failure patients undergoing cardiac resynchronization therapy (VISION-CRT). Impact of current versus previous cardiac resynchronization therapy guidelines on the proportion of patients with heart failure eligible for therapy. [Extracted from the article]

Objective: To compare the frequency of transient arterial-phase respiratory-motion-related artifacts in liver MRI after extracellular gadolinium and gadoxetic acid injection, and to determine the impact of these artifacts on the detection of focal areas of enhancement on arterial-phase images. Materials and methods: Intra-patient comparison of 82 cirrhotic patients who prospectively underwent liver MR with extracellular gadolinium and with gadoxetic acid within 1 month. Two readers independently assessed the quality of dynamic T1-weighted MR images (pre-contrast, arterial, and portal-venous phases), rating respiratory-motion-related artifacts on four-point scale (0 [none]–3 [non-diagnostic]). We dichotomized these assessments, which were compared using McNemar's test, defining transient arterial-phase respiratory-motion-related artifacts as a study with a pre-contrast score < 2 and arterial-phase score ≥ 2. Readers also recorded whether at least one focal area of enhancement ≥ 10 mm on arterial phase was present. Results: The quality of arterial-phase images was worse when obtained after gadoxetic acid than after extracellular gadolinium (p < 0.01), and transient arterial-phase respiratory-motion-related artifacts were more common after gadoxetic acid than after extracellular gadolinium (p < 0.02). At least one area of arterial-phase enhancement ≥ 10 mm was detected more often after extracellular gadolinium than after gadoxetic acid. We observed significant differences on the comparison of the distributions of the presence of arterial-phase artifacts against the presence of arterial-phase enhancement ≥ 10 mm between the two contrast agents (p < 0.0001). Conclusion: In cirrhotic patients, transient arterial-phase respiratory-motion-related artifacts are more common after gadoxetic acid than after extracellular gadolinium. Worse detection of arterial-phase enhancement on gadoxetic acid is only partly due to these artifacts. Key Points: • In a patient-by-patient analysis, the quality of arterial-phase liver MR images was significantly worse with gadoxetic acid than with extracellular gadolinium. • The frequency of transient arterial-phase artifacts was significantly higher after gadoxetic acid injection than after extracellular gadolinium injection. • Differences in the detection of areas of arterial-phase enhancement between MRI studies done with extracellular gadolinium and those done with gadoxetic acid might not be related only to image quality. [ABSTRACT FROM AUTHOR]

Introduction: Intrahepatic cholangiocarcinoma (ICC) is a rare type of liver cancer. "Very early" ICC, defined as a solitary lesion of ≤ 2 cm in diameter, appears to have a favorable outcome. Purpose: This study aimed to assess the outcome of patients with "very early" ICC treated with curative surgical resection in an intention-to-treat analysis. Methods: All patients with ICC undergoing surgical resection at the Hospital Clínic of Barcelona (Spain) between April 2000 and December 2018 were reviewed, and those with evident "very early" ICC in preoperative imaging studies were selected. Results of histopathologic examination of the surgical specimen, postoperative complications, recurrence, and survival were assessed. Results: Of the 89 patients operated for ICC during the study period, 7 (7.9%) met the "very early" criteria at preoperative imaging. Two (TNM 7th) and four (TNM 8th) patients were classified as stage I, following histological examination of their resected specimens. One patient presented with postoperative morbidity (grade II Clavien-Dindo). The median (IQR) hospital stay was 5 days (3–7). After a median follow-up of 23 months (IQR 11.9–80.6), recurrence was diagnosed in one case at 8.3 months after surgery. The overall survival at 1, 3, and 5 years was 85.7%, 68.6%, and 68.6%, respectively. Conclusion: Intention-to-treat curative surgery in "very early" ICC is associated with good results in terms of survival and recurrence. However, most patients presented more advanced stages in the definitive pathological analysis, associated with a lower survival. Future prospective multicenter studies are required to validate these encouraging data. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases are the leading cause of death worldwide. Changes in lifestyle and/or pharmacological treatment are able to reduce the burden of coronary artery diseases (CAD) and early diagnosis is crucial for the timely and optimal management of the disease. Stress testing is a good method to measure the burden of CAD but it is time consuming and pharmacological testing may not fully mimic exercise test. The objectives of the present project were to characterize the metabolic profile of the population undergoing pharmacological and exercise stress testing to evaluate possible differences between them, and to assess the capacity of 1H NMR spectroscopy to predict positive stress testing. Pattern recognition was applied to 1H NMR spectra from serum of patients undergoing stress test and metabolites were quantified. The effects of the stress test, confounding variables and the ability to predict ischemia were evaluated using OPLS-DA. There was an increase in lactate and alanine concentrations in post-test samples in patients undergoing exercise test, but not in those submitted to pharmacological testing. However, when considering only pharmacological patients, those with a positive test result, showed increased serum lactate, that was masked by the much larger amount of lactate associated to exercise testing. In conclusion, we have established that pharmacological stress test does not reproduce the dynamic changes observed in exercise stress. Although there is promising evidence suggesting that 1H NMR based metabolomics could predict stress test results, further studies with much larger populations will be required in order to obtain a definitive answer. [ABSTRACT FROM AUTHOR]

Background & Aims: Sorafenib and lenvatinib are the first‐line treatments approved in hepatocellular carcinoma (HCC), but information is lacking about the relationships between their pharmacokinetics, patients pharmacogenetic profiles, adverse events (AE) and overall survival. We aimed to elucidate these relationships of tyrosine Kinase Inhibitors, such as sorafenib, in order to improve the design of trials testing it in combination with checkpoint inhibitors. Methods: We assessed the pharmacokinetics of sorafenib and its N‐oxide metabolite at day‐0, day‐7, day‐30, day‐60, day‐90, day‐120, day‐150 and day‐180 and nine single‐nucleotide polymorphisms (SNP) in five genes related to sorafenib metabolism/transport to identify the best point for starting the combination between tyrosine kinases and checkpoint inhibitors. Results: We prospectively included 49 patients (96% cirrhotic, 37% hepatitis‐C, 82% Child‐Pugh‐A and 59% BCLC‐C). Pharmacokinetic values peaked at day‐7 and progressively declined until day‐60. In the 16 patients without further dose modifications after day‐60, pharmacokinetic values remained stable through day‐180 (sorafenib P =.90; N‐oxide P =.93). Pharmacokinetic values were higher in patients with early dermatological adverse events and lower in patients with early diarrhoea. Sorafenib and N‐oxide pharmacokinetic values varied linearly with different alleles of MRP2*3972. Conclusions: Sorafenib's pharmacokinetics is heterogeneous across HCC patients. This heterogeneity affects adverse events development and must be taken into account in setting the dose and timing of its combination with checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Análisis de la relación coste-efectividad (RCE) del electrocardiograma de esfuerzo y de la SPECT de perfusión miocárdica esfuerzo-reposo en relación con la revascularización coronaria (RC), eventos cardíacos (EC) y mortalidad total (MT). Se estudiaron 8.496 pacientes con SPECT y seguimiento medio de 5,3 ± 3,5 años. Evaluamos la RCE para la RC quirúrgica (RCQ) y percutánea (RCP) (45,6%/54,4%) de acuerdo con los resultados de la isquemia electrocardiográfica y gammagráfica. La efectividad se evaluó como MT, EC, LYSO (life-year-saved-observed) y EC-LYSO. Los análisis de costes se realizaron desde la perspectiva del pagador de atención médica. El análisis de sensibilidad fue considerando las relaciones RCQ/RCP actuales (12%/88%). Al combinar los resultados del electrocardiograma de esfuerzo y de la gammagrafía, los valores de coste-efectividad para la RCQ variaron entre 112.589 € (isquemia electrocardiográfica y gammagráfica) y 2.814.715 € (sin isquemia)/evento evitado, y entre 38.664 y 2.221.559 €/LYSO; y para la RCP entre 18.824 € (isquemia electrocardiográfica y gammagráfica) y 46.377 € (sin isquemia)/evento evitado, y entre 6.464 y 36.604 €/LYSO. Para el EC: los valores de coste-efectividad de la RCQ y RCP en presencia de isquemia electrocardiográfica y gammagráfica fueron de 269.904 €/EC evitado y de 24.428 €/EC evitado, respectivamente; y los €/LYSO de la RCQ y RCP fueron de 152.488 y 13.801, respectivamente. Se mantuvo la misma RCE para la proporción actual de pacientes revascularizados (12%/88%). El análisis combinado de las imágenes de la SPECT y del electrocardiograma de esfuerzo permite la diferenciación entre grupos de pacientes en donde la RCP y la RCQ son más rentables. La mayor RCE en relación con la RC, EC y MT se da en los pacientes con isquemia electrocardiográfica y gammagráfica. La RCP es más coste-efectiva que la RCQ. The aim was to analyze the cost-effectiveness ratio (CER) of stress electrocardiogram (ES) and stress myocardial perfusion imaging (SPECT-MPI) according to coronary revascularization (CR) therapy, cardiac events (CE) and total mortality (TM). A total of 8,496 consecutive patients who underwent SPECT-MPI were followed-up (mean 5.3 ± 3.5 years). Cost-effectiveness for coronary bypass (CABG) or percutaneous CR (PCR) (45.6%/54.4%) according to combined electrocardiographic ischemia and scintigraphic ischemia were evaluated. Effectiveness was evaluated as TM, CE, life-year saved observed (LYSO) and CE-LYSO; costs analyses were conducted from the perspective of the health care payer. A sensitivity analysis was performed considering current CABG/PCR ratios (12%/88%). When electrocardiogram and SPECT approaches are combined, the cost-effectiveness values for CABG ranged between 112,589 € (electrocardiographic and scintigraphic ischemia) and 2,814,715 € (without ischemia)/event avoided, 38,664 and 2,221,559 €/LYSO; for PCR ranged between 18,824 € (electrocardiographic and scintigraphic ischemia) and 46,377 € (without ischemia)/event avoided, 6,464 and 36,604 €/LYSO. To CE: the cost-effectiveness values of the CABG and CPR in presence of electrocardiographic and scintigraphic ischemia were 269,904 €/CE-avoided and 24,428 €/CE-avoided, respectively; and the €/LYSO of the CABG and PCR were 152,488 and 13,801, respectively. The RCE was maintained for the current proportion of revascularized patients (12%/88%). Combined ES and SPECT-MPI results, allows differentiation between patient groups, where the PCR and CABG are more cost-effective in different economic frameworks. The major CER in relation to CR, CE and TM occurs in patients with electrocardiographic and scintigraphic ischemia. PCR is more cost-effective than CABG. [ABSTRACT FROM AUTHOR]