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Varios estudios han investigado la eficacia de guiarse por la reserva fraccional de flujo (RFF) para mejorar los resultados clínicos tras la revascularización miocárdica, con resultados contradictorios. El objetivo es comparar los resultados clínicos en pacientes con enfermedad coronaria tras una revascularización guiada por RFF o por angiografía.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children. Roughly a quarter of paediatric patients with NAFLD develop nonalcoholic steatohepatitis and fibrosis. Here, we evaluated the diagnostic accuracy of previously published noninvasive fibrosis scores to predict liver fibrosis in a large European cohort of paediatric patients with NAFLD. The 457 patients with biopsy‐proven NAFLD from 10 specialized centers were included. We assessed diagnostic accuracy for the prediction of any (F ≥ 1), moderate (F ≥ 2) or advanced (F ≥ 3) fibrosis for the AST/platelet ratio (APRI), Fibrosis 4 score (FIB‐4), paediatric NAFLD fibrosis score (PNFS) and paediatric NAFLD fibrosis index (PNFI). Patients covered the full spectrum of fibrosis (F0: n= 103; F1: n= 230; F2: n= 78; F3: n= 44; F4: n= 2). None of the scores were able to accurately distinguish the presence of any fibrosis from no fibrosis. For the detection of moderate fibrosis, area under the receiver operating characteristic curve (AUROC) were: APRI: 0.697, FIB‐4: 0.663, PNFI: 0.515, PNFS: 0.665, while for detection of advanced fibrosis AUROCs were: APRI: 0.759, FIB‐4: 0.611, PNFI: 0.521, PNFS: 0.712. Fibrosis scores showed no diagnostic benefit over using ALT ≤ 50/ > 50 IU/L as a cut‐off. Established fibrosis scores lack diagnostic accuracy to replace liver biopsy for staging of fibrosis, giving similar results as compared to using ALT alone. New diagnostic tools are needed for Noninvasive risk‐stratification in paediatric NAFLD. The high prevalence of nonalcoholic fatty liver disease (NAFLD) in children and its risk for the development of fibrosis and serious hepatic complications prompt the need for noninvasive monitoring tools.Noninvasive fibrosis scores are well validated in adult populations with NAFLD, while data on diagnostic utility in children and adolescents is limited. The high prevalence of nonalcoholic fatty liver disease (NAFLD) in children and its risk for the development of fibrosis and serious hepatic complications prompt the need for noninvasive monitoring tools. Noninvasive fibrosis scores are well validated in adult populations with NAFLD, while data on diagnostic utility in children and adolescents is limited. No fibrosis score accurately distinguished fibrosis from no fibrosis.For the detection of higher fibrosis stages, available fibrosis score systems show no advantage over the sole use of alanine aminotransferase (ALT). No fibrosis score accurately distinguished fibrosis from no fibrosis. For the detection of higher fibrosis stages, available fibrosis score systems show no advantage over the sole use of alanine aminotransferase (ALT).

ObjectiveTo compare the effects of ticagrelor and prasugrel on absolute coronary blood flow (Q) and microvascular resistance (R) in patients with stable coronary artery disease (CAD) treated with elective percutaneous coronary intervention (PCI) (NCT05643586). Besides being at least as effective as prasugrel in inhibiting platelet aggregation, ticagrelor has been shown to have additional properties potentially affecting coronary microcirculation.MethodsWe randomly assigned 50 patients to ticagrelor (180 mg) or prasugrel (60 mg) at least 12 hours before intervention. Continuous thermodilution was used to measure Q and R before and after PCI. Platelet reactivity was measured before PCI. Troponin I was measured before, 8 and 24 hours after PCI.ResultsAt baseline, fractional flow reserve, Q and R were similar in two study groups. Patients in the ticagrelor group showed higher post-PCI Q (242±49 vs 205±53 mL/min, p=0.015) and lower R values (311 (263, 366) vs 362 (319, 382) mm Hg/L/min, p=0.032). Platelet reactivity showed a negative correlation with periprocedural variation of Q values (r=−0.582, p<0.001) and a positive correlation with periprocedural variation of R values (r=0.645, p<0.001). The periprocedural increase in high-sensitivity troponin I was significantly lower in the ticagrelor compared with the prasugrel group (5 (4, 9) ng/mL vs 14 (10, 24) ng/mL, p<0.001).ConclusionsIn patients with stable CAD undergoing PCI, pretreatment with a loading dose of ticagrelor compared with prasugrel improves post-procedural coronary flow and microvascular function and seems to reduce the related myocardial injury.

IMPORTANCE: Trials showing equivalent or better outcomes with initial evaluation using coronary computed tomography angiography (cCTA) compared with stress testing in patients with stable chest pain have informed guidelines but raise questions about overtesting and excess catheterization. OBJECTIVE: To test a modified initial cCTA strategy designed to improve clinical efficiency vs usual testing (UT). DESIGN, SETTING, AND PARTICIPANTS: This was a pragmatic randomized clinical trial enrolling participants from December 3, 2018, to May 18, 2021, with a median of 11.8 months of follow-up. Patients from 65 North American and European sites with stable symptoms of suspected coronary artery disease (CAD) and no prior testing were randomly assigned 1:1 to precision strategy (PS) or UT. INTERVENTIONS: PS incorporated the Prospective Multicenter Imaging Study for the Evaluation of Chest Pain (PROMISE) minimal risk score to quantitatively select minimal-risk participants for deferred testing, assigning all others to cCTA with selective CT-derived fractional flow reserve (FFR-CT). UT included site-selected stress testing or catheterization. Site clinicians determined subsequent care. MAIN OUTCOMES AND MEASURES: Outcomes were clinical efficiency (invasive catheterization without obstructive CAD) and safety (death or nonfatal myocardial infarction [MI]) combined into a composite primary end point. Secondary end points included safety components of the primary outcome and medication use. RESULTS: A total of 2103 participants (mean [SD] age, 58.4 [11.5] years; 1056 male [50.2%]) were included in the study, and 422 [20.1%] were classified as minimal risk. The primary end point occurred in 44 of 1057 participants (4.2%) in the PS group and in 118 of 1046 participants (11.3%) in the UT group (hazard ratio [HR], 0.35; 95% CI, 0.25-0.50). Clinical efficiency was higher with PS, with lower rates of catheterization without obstructive disease (27 [2.6%]) vs UT participants (107 [10.2%]; HR, 0.24; 95% CI, 0.16-0.36). The safety composite of death/MI was similar (HR, 1.52; 95% CI, 0.73-3.15). Death occurred in 5 individuals (0.5%) in the PS group vs 7 (0.7%) in the UT group (HR, 0.71; 95% CI, 0.23-2.23), and nonfatal MI occurred in 13 individuals (1.2%) in the PS group vs 5 (0.5%) in the UT group (HR, 2.65; 95% CI, 0.96-7.36). Use of lipid-lowering (450 of 900 [50.0%] vs 365 of 873 [41.8%]) and antiplatelet (321 of 900 [35.7%] vs 237 of 873 [27.1%]) medications at 1 year was higher in the PS group compared with the UT group (both P &lt; .001). CONCLUSIONS AND RELEVANCE: An initial diagnostic approach to stable chest pain starting with quantitative risk stratification and deferred testing for minimal-risk patients and cCTA with selective FFR-CT in all others increased clinical efficiency relative to UT at 1 year. Additional randomized clinical trials are needed to verify these findings, including safety. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03702244

IMPORTANCE: Guidelines recommend deferral of testing for symptomatic people with suspected coronary artery disease (CAD) and low pretest probability. To our knowledge, no randomized trial has prospectively evaluated such a strategy. OBJECTIVE: To assess process of care and health outcomes in people identified as minimal risk for CAD when testing is deferred. DESIGN, SETTING, AND PARTICIPANTS: This randomized, pragmatic effectiveness trial included prespecified subgroup analysis of the PRECISE trial at 65 North American and European sites. Participants identified as minimal risk by the validated PROMISE minimal risk score (PMRS) were included. INTERVENTION: Randomization to a precision strategy using the PMRS to assign those with minimal risk to deferred testing and others to coronary computed tomography angiography with selective computed tomography-derived fractional flow reserve, or to usual testing (stress testing or catheterization with PMRS masked). Randomization was stratified by PMRS risk. MAIN OUTCOME: Composite of all-cause death, nonfatal myocardial infarction (MI), or catheterization without obstructive CAD through 12 months. RESULTS: Among 2103 participants, 422 were identified as minimal risk (20%) and randomized to deferred testing (n = 214) or usual testing (n = 208). Mean age (SD) was 46 (8.6) years; 304 were women (72%). During follow-up, 138 of those randomized to deferred testing never had testing (64%), whereas 76 had a downstream test (36%) (at median [IQR] 48 [15-78] days) for worsening (30%), uncontrolled (10%), or new symptoms (6%), or changing clinician preference (19%) or participant preference (10%). Results were normal for 96% of these tests. The primary end point occurred in 2 deferred testing (0.9%) and 13 usual testing participants (6.3%) (hazard ratio, 0.15; 95% CI, 0.03-0.66; P = .01). No death or MI was observed in the deferred testing participants, while 1 noncardiovascular death and 1 MI occurred in the usual testing group. Two participants (0.9%) had catheterizations without obstructive CAD in the deferred testing group and 12 (5.8%) with usual testing (P = .02). At baseline, 70% of participants had frequent angina and there was similar reduction of frequent angina to less than 20% at 12 months in both groups. CONCLUSION AND RELEVANCE: In symptomatic participants with suspected CAD, identification of minimal risk by the PMRS guided a strategy of initially deferred testing. The strategy was safe with no observed adverse outcome events, fewer catheterizations without obstructive CAD, and similar symptom relief compared with usual testing. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03702244

AbstractBackgroundMinimally invasive procedures for coronary revascularization have been performed for over 20 years; however, their technical complexity, steep learning curves and absence of training programs explain the weak acceptance of these techniques. The aim of this study is to describe the step-by-step learning process on how to establish a minimally invasive coronary artery revascularization program. The short-term outcomes of our first 30 patients were compared to our left internal mammary artery (LIMA) to left anterior descending (LAD) artery off pump coronary artery bypass (OPCAB) cohort as a quality control baseline.MethodsAll patients who benefited from an endoscopic atraumatic coronary artery bypass (Endo-ACAB) in our hospital, from July 2018 to May 2020 (n = 30) were identified. Baseline demographics, peri, postoperative and laboratory data were extracted from each patient’s medical records. These results were compared to our LIMA-LAD OPCAB cohort (n = 23).ResultsTwenty-eight patients were planned for a single LIMA-LAD Endo-ACAB. The remaining two had a T-graft double Endo-ACAB. Ten patients had a hybrid revascularization with the culprit lesion being treated first. Three patients were converted to sternotomy because of a LIMA lesion during thoracoscopic harvesting. We accounted three major adverse cardiovascular events (MACE). Demographic, peri and postoperative data showed no significant differences between the Endo-ACAB and the OPCAB group.ConclusionEndo-ACAB is a technically demanding operation, however, it can safely be introduced in centers with no previous experience with no extra cost in terms of morbidity or mortality. Thoracoscopic LIMA harvesting is the most demanding surgical skill to acquire.

IMPORTANCE: Titanium-nitride-oxide (TiNO)–coated stents show faster strut coverage compared with drug-eluting stents without excessive intimal-hyperplasia observed in bare metal stents. It is important to study long-term clinical outcomes after treatment of patients with an acute coronary syndrome (ACS) by TiNO-coated stents, which are neither drug-eluting stents nor bare metal stents. OBJECTIVE: To compare the rate of main composite outcome of cardiac death, myocardial infarction (MI), or ischemia-driven target lesion revascularization at 5 years in patients with ACS randomized to receive either a TiNO-coated stent or a third-generation everolimus-eluting stent (EES). DESIGN, SETTING, AND PARTICIPANTS: This multicenter, randomized, controlled, open-label trial was conducted in 12 clinical sites in 5 European countries and enrolled patients from January 2014 to August 2016. Patients presenting with ACS (ST-segment elevation MI, non–ST-segment elevation MI, and unstable angina) with at least 1 de novo lesion were randomized to receive either a TiNO-coated stent or an EES. The present report analyzes the long-term follow-up for the main composite outcome and its individual components. Analysis took place between November 2022 to March 2023. MAIN OUTCOME: The primary end point was a composite of cardiac death, MI, or target lesion revascularization at 12-month follow-up. RESULTS: A total of 1491 patients with ACS were randomly assigned to receive either TiNO-coated stents (989 [66.3%]) or EES (502 [33.7%]). The mean (SD) age was 62.7 (10.8) years, and 363 (24.3%) were female. At 5 years, the main composite outcome events occurred in 111 patients (11.2%) in the TiNO group vs 60 patients (12%) in the EES group (hazard ratio [HR], 0.94; 95% CI, 0.69-1.28; P = .69). The rate of cardiac death was 0.9% (9 of 989) vs 3.0% (15 of 502) (HR, 0.30; 95% CI, 0.13-0.69; P = .005), the rate of MI was 4.6% (45 of 989) vs 7.0% (35 of 502) (HR, 0.64; 95% CI, 0.41-0.99; P = .049), the rate of stent thrombosis was 1.2% (12 of 989) vs 2.8% (14 of 502) (HR, 0.43; 95% CI, 0.20-0.93; P = .034), and the rate of target lesion revascularization was 7.4% (73 of 989) vs 6.4% (32 of 502) (HR, 1.16; 95% CI, 0.77-1.76; P = .47) in the TiNO-coated stent arm and in the EES arm, respectively. CONCLUSION AND RELEVANCE: In this study, patients with ACS had a main composite outcome that was not different 5 years after TiNO-coated stent or EES. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02049229

Evaluar mediante tomografía de coherencia óptica (OCT) el proceso de cicatrización neointimal tras el implante de stentsde cromo cobalto con recubrimiento de titanio-óxido nítrico (TiNO) y de stentsde platino-cromo liberadores de everolimus (SLE) con polímero biodegradable en pacientes con síndrome coronario agudo.

BackgroundDevelopment of left ventricle (LV) hypertrophy in aortic stenosis (AS) is accompanied by adaptive coronary flow regulation. We aimed to assess absolute coronary flow, microvascular resistance, coronary flow reverse (CFR) and microvascular resistance reserve (MRR) in patients with and without AS.MethodsAbsolute coronary flow and microvascular resistance were measured by continuous thermodilution in 29 patients with AS and 29 controls, without AS, matched for age, gender, diabetes and functional severity of epicardial coronary lesions. Myocardial work, total myocardial mass and left anterior descending artery (LAD)-specific mass were quantified by echocardiography and cardiac-CT.ResultsPatients with AS presented a significantly positive LV remodelling with lower global longitudinal strain and global work efficacy compared with controls. Total LV myocardial mass and LAD-specific myocardial mass were significantly higher in patients with AS (p=0.001). Compared with matched controls, absolute resting flow in the LAD was significantly higher in the AS cohort (p=0.009), resulting into lower CFR and MRR in the AS cohort compared with controls (p<0.005 for both). No differences were found in hyperaemic flow and resting and hyperaemic resistances. Hyperaemic myocardial perfusion (calculated as the ratio between the absolute coronary flow subtended to the LAD, expressed in mL/min/g), but not resting, was significantly lower in the AS group (p=0.035).ConclusionsIn patients with severe AS and non-obstructive coronary artery disease, with the progression of LV hypertrophy, the compensatory mechanism of increased resting flow maintains adequate perfusion at rest, but not during hyperaemia. As a consequence, both CFR and MRR are significantly impaired.

Endomyocardial biopsy (EMB) facilitates a histopathologic diagnosis with unique prognostic and therapeutic implications in both native and donor hearts. It is a relatively safe procedure, with an overall complication rate ranging from <1% to 6% depending on the experience of the operator, the clinical status of the patient, the presence or absence of left bundle branch block, the access site, and the site of procurement (right ventricular [RV] vs left ventricular [LV] approach).

Background: Anastomotic leakage (AL) after Ivor Lewis esophagectomy with intrathoracic anastomosis carries a significant morbidity. Adequate perfusion of the gastric tube (GT) is an important predictor of anastomotic integrity. Recently, near infrared fluorescent (NIRF) imaging using indocyanine green (ICG) was introduced in clinical practice to evaluate tissue perfusion. We evaluated the feasibility and efficacy of GT indocyanine green angiography (ICGA) after Ivor Lewis esophagectomy. Methods: This retrospective analysis used data from a prospectively kept database of consecutive patients who underwent Ivor Lewis (IL) esophagectomy with GT construction for cancer between January 2016 and December 2020. Relevant outcomes were feasibility, ICGA complications and the impact of ICGA on AL. Results: 266 consecutive IL patients were identified who matched the inclusion criteria. The 115 patients operated with perioperative ICGA were compared to a control group in whom surgery was performed according to the standard of care. ICGA perfusion assessment was feasible and safe in all 115 procedures and suggested a poorly perfused tip in 56/115 (48.7%) cases, for which additional resection was performed. The overall AL rate was 16% (43/266), with 12% (33/266) needing an endoscopic our surgical intervention and 6% (17/266) needing ICU support. In univariable and multivariable analyses, ICGA was not correlated with the risk of AL (ICGA:14.8% vs non-ICGA:17.2%, p= 0.62). However, poor ICGA perfusion of the GT predicted a higher AL rate, despite additional resection of the tip (ICGA poorly perfused: 19.6% vs ICG well perfused: 10.2%, p= 0.19). Conclusions: ICGA is safe and feasible, but did not result in a reduction of AL. The interpretation and necessary action in case of perioperative presence of ischemia on ICGA have yet to be determined. Prospective randomized trials are warranted to analyze its benefit on AL in esophageal surgery.

Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in children and adolescents, particularly those with obesity. NAFLD is considered a hepatic manifestation of the metabolic syndrome due to its close associations with abdominal obesity, insulin resistance, and atherogenic dyslipidemia. Experts have proposed an alternative terminology, metabolic dysfunction-associated fatty liver disease (MAFLD), to better reflect its pathophysiology. This study aimed to develop consensus statements and recommendations for pediatric MAFLD through collaboration among international experts.

IntroductionMedical devices (MedDevs) and medicines are assessed (and monitored) differently before and after launch. There are products for repeated oral ingestion that are marketed in the European Union as MedDevs.Objectives and methodsTo illustrate the consequences of these differences in assessment, we compared the leaflet information of three MedDevs with the standards for medicines and with published evidence at launch. As examples, gelatin tannate (GT), its combination with tyndalised probiotics (TP) (GTTP) for diarrhoea and a gel containing hyaluronic acid (HA)/chondroitin sulfate (CS)/poloxamer (Pol407) (HACSPol) for gastro-oesophageal reflux disease were examined.ResultsApplying standards for medicines, product composition is insufficiently defined in the MedDev leaflet (eg, plant origin, polymerisation grade, dose and ratio of the relevant constituents). As no age limit is mentioned in the leaflets, all 3 products allow use in children from birth onwards, although published clinical documentation in children was poor (GT) or lacking (GTTP and HACSPol). MedDev leaflets do not mention adverse events (AEs), while literature search suggests safety concerns such as tannic acid (TA) cytotoxicity, potentially more diarrhoea/AEs with TP, use of doses higher than established safe (TA and HA) and lack of chronic toxicity studies for oral Pol407. None refers to interactions with medicines, although some ingredients may affect medicine absorption.ConclusionAlthough these MedDevs require repeated oral intake as do medicines, their assessment and monitoring differ significantly from the standards for medicines. Compared with medicines, MedDevs for repeated oral use are poorly labelled and rely on very limited clinical information at market release.

This paper develops, and then applies, a holistic framework that supports industrial policy decision-making at the global value chain (GVC) level, with the aim of stimulating sustainable developmentin developing countries. Notwithstanding the importance of economic growth for development, industrial policy decision-makers are also concerned about social and environmental objectives when setting industrial policies. We develop a framework that allows for a trade-off between economic growth, social objectives, and environmental goals. We do so by building on the established product space literature, and its extensions, and applying it to the value chain level using the input-output product space approach. By including emerging environmental and green metrics, we manage to identify Pareto-optimal industry targets, taking the economic, environmental, and social objectives simultaneously into account. At the same time, expected required government investment is minimized. Finally, we apply our new framework to the specific case of iron and steel in the Southern African Customs Union, and draw lessons for future work from this example.

Recent years have seen renewed interest in evaluating the effectiveness of industrial policy, especially in the context of global value chains. One approach that might add a complementary view in this domain is product space analysis. To date, product space-based value chain analyses have focused on theoretical debates only, or on empirical applications for a single year. In this paper, we employ the input–output product space (IO–PS) framework combined with a time dimension. We thereby evaluate the effectiveness of industrial policies within a value chain over time. The paper focuses on the case of the South African automotive value chain for the years 1995 to 2017. We evaluate ex post the implemented industrial policies and confirm their (partial) success. We then use the framework to make ex ante recommendations to improve the current policy approach and find that it might pay off to target specific sub-sectors in the future. The results illustrate how the framework can be used to evaluate industrial policies and to identify which parts of the global value chain should be targeted to foster both short- and long-term growth. We also highlight shortcomings of the approach which might limit its application.

La métabolomique s’est largement imposée comme une mesure sensible et dynamique d’un phénotype au niveau moléculaire. Elle présente un intérêt particulier pour les biologistes médicaux et les cliniciens comme outil prometteur pour l’identification de potentiels biomarqueurs à visée de diagnostic, de pronostic, ou prédictifs d’états pathologiques, ou encore pour l’élucidation de mécanismes liés à des processus physiopathologiques, y compris en toxicologie [Lenski M. et al. Toxicol Anal Clin 2023;35:96-112]. L’analyse métabolomique est dite ciblée lorsqu’une ou plusieurs voies métaboliques d’intérêt sont spécifiquement étudiées. À l’inverse, l’approche non ciblée est l’étude complète de tous les métabolites détectables dans un échantillon biologique, permettant une vision plus globale de la réponse biologique suite à un stimulus d’intérêt. Actuellement, la métabolomique est principalement mise en œuvre en recherche, mais son utilisation en routine en laboratoire de biologie médicale n’est pas clairement établie. La répartition des différents domaines d’application de la métabolomique clinique est également inconnue.

AbstractA 71-year-old female with symptomatic bitroncular coronary ischemic disease was admitted in our hospital for hybrid revascularization. She presented significant stenosis of the proximal and middle left anterior descending artery (LAD) and of the second segment of right coronary artery (RCA). She was scheduled for an Endoscopic Atraumatic Coronary Artery Bypass (EACAB) of the left internal mammary artery (LIMA) to LAD and staged percutaneous coronary intervention (PCI) to RCA after the EACAB. Control of LIMA permeability after RCA PCI showed LIMA dissection with TIMI 2 flow to LAD. Decision to stent a freshly implanted LIMA led to LIMA rupture. An emergent LAD revascularization with a saphenous vein graft and control of bleeding was successfully performed. Patient was discharged at day 10 from the hospital.

Multiple myeloma (MM) is an (epi)genetic highly heterogeneous plasma cell malignancy that remains mostly incurable. Deregulated expression and/or genetic defects in epigenetic-modifying enzymes contribute to high-risk disease and MM progression. Overexpression of the histone methyltransferase G9a was reported in several cancers, including MM, correlating with disease progression, metastasis, and poor prognosis. However, the exact role of G9a and its interaction partner G9a-like protein (GLP) in MM biology and the underlying mechanisms of action remain poorly understood. Here, we report that high G9a RNA levels are associated with a worse disease outcome in newly diagnosed and relapsed MM patients. G9a/GLP targeting using the specific G9a/GLP inhibitors BIX01294 and UNC0638 induces a G1-phase arrest and apoptosis in MM cell lines and reduces primary MM cell viability. Mechanistic studies revealed that G9a/GLP targeting promotes autophagy-associated apoptosis by inactivating the mTOR/4EBP1 pathway and reducing c-MYC levels. Moreover, genes deregulated by G9a/GLP targeting are associated with repressive histone marks. G9a/GLP targeting sensitizes MM cells to the proteasome inhibitors (PIs) bortezomib and carfilzomib, by (further) reducing mTOR signaling and c-MYC levels and activating p-38 and SAPK/JNK signaling. Therapeutic treatment of 5TGM1 mice with BIX01294 delayed in vivo MM tumor growth, and cotreatment with bortezomib resulted in a further reduction in tumor burden and a significantly prolonged survival. In conclusion, we provide evidence that the histone methyltransferases G9a/GLP support MM cell growth and survival by blocking basal autophagy and sustaining high c-MYC levels. G9a/GLP targeting represents a promising strategy to improve PI-based treatment in patients with high G9a/GLP levels.

Multiple myeloma (MM) is an (epi)genetic highly heterogeneous plasma cell malignancy that remains mostly incurable. Deregulated expression and/or genetic defects in epigenetic-modifying enzymes contribute to high-risk disease and MM progression. Overexpression of the histone methyltransferase G9a was reported in several cancers, including MM, correlating with disease progression, metastasis, and poor prognosis. However, the exact role of G9a and its interaction partner G9a-like protein (GLP) in MM biology and the underlying mechanisms of action remain poorly understood. Here, we report that high G9a RNA levels are associated with a worse disease outcome in newly diagnosed and relapsed MM patients. G9a/GLP targeting using the specific G9a/GLP inhibitors BIX01294 and UNC0638 induces a G1-phase arrest and apoptosis in MM cell lines and reduces primary MM cell viability. Mechanistic studies revealed that G9a/GLP targeting promotes autophagy-associated apoptosis by inactivating the mTOR/4EBP1 pathway and reducing c-MYC levels. Moreover, genes deregulated by G9a/GLP targeting are associated with repressive histone marks. G9a/GLP targeting sensitizes MM cells to the proteasome inhibitors (PIs) bortezomib and carfilzomib, by (further) reducing mTOR signaling and c-MYC levels and activating p-38 and SAPK/JNK signaling. Therapeutic treatment of 5TGM1 mice with BIX01294 delayed in vivo MM tumor growth, and cotreatment with bortezomib resulted in a further reduction in tumor burden and a significantly prolonged survival. In conclusion, we provide evidence that the histone methyltransferases G9a/GLP support MM cell growth and survival by blocking basal autophagy and sustaining high c-MYC levels. G9a/GLP targeting represents a promising strategy to improve PI-based treatment in patients with high G9a/GLP levels.

Autoantibodies (AAb) and donor-specific HLA antibodies (DSA) are frequently present in pediatric liver transplant (LT) recipients. Their clinical significance remains incompletely understood. We aimed to investigate the prevalence of serum AAb and DSA in pediatric LT recipients and its correlation with patient characteristics and histological and biochemical parameters. We retrospectively reviewed the data from 62 pediatric LT patients in follow-up at Ghent University Hospital between January 2007 and February 2018. Blood samples with AAb measurement were taken systematically, liver biopsies (LB) were performed on clinical indication. AAb were detected in 27 (43.3%) patients, with antinuclear antibodies (ANA) being the most frequently (24%) encountered AAb. There was an association between AAb positivity and female gender (P= 0,032) and deceased donor LT (P= 0,006). Patients with positive AAb underwent a higher number of LB during their follow-up (P< 0,001), and an association was found with the presence of nonspecific histologic alterations (P= 0,032) in the absence of de novoautoimmune hepatitis. Positive AAb were also associated with higher alkaline phosphatase (P< 0,001), ALT (P< 0,001), AST (P< 0,001), ?-GT (P= 0,001), IgG (P= 0,011) and lower albumin (P= 0,029). Fourteen out of 50 (28%) patients were DSA-positive, mostly anti-HLA class II. DSA positivity was associated with T-cell-mediated rejection (P= 0,019), higher total (P= 0,033), and direct (P= 0,012) bilirubin and ?-GT (P< 0,001). The presence of AAb and DSA is associated with histological and biochemical parameters of graft dysfunction. Larger prospective studies are warranted to investigate the causal relationships between AAb and DSA development and outcome parameters post pediatric LT.

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Respiratory syncytial virus (RSV) is the most common cause of severe lower respiratory tract infection, with a high global health burden. There are no effective treatments available. ALX-0171 is a novel trivalent Nanobody with antiviral properties against RSV. We aimed to assess the safety and antiviral activity of nebulised ALX-0171 in children admitted to hospital with RSV lower respiratory tract infection.

ObjectiveTo study the pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of desmopressin (dDAVP) oral lyophilisate in children below the age of 8 years with special emphasis on age-related and size-related differences in bioavailability.DesignOpen label, non-randomised, interventional PK and PD trial.SettingSingle-centre study.PatientsChildren (age: 6 months to 8 years) with nocturnal polyuria, including both children with uropathy or nephropathy (glomerular filtration rate >60 mL/min/1.73 m²) and children (age: 5–8 years) with severe monosymptomatic nocturnal enuresis, who were unresponsive to treatment with 400 µg of the dDAVP tablet for at least 1 month.InterventionsAfter a water load, dDAVP was administered sublingually as a single dose of oral lyophilisate. Subsequently, blood and urine samples were collected until 7 hours post-administration.Main outcome measuresNon-compartmental analysis of PK parameters was performed based on dDAVP concentrations in both plasma and urine. To evaluate the effect of dDAVP lyophilisate (PD parameters), the urinary concentration capacity (urine osmolality (mOsm/kg)) and antidiuretic effect (diuresis rate (mL/kg/h)) were calculated.ResultsThe PK data support the need for size-dependent dosing in children. Body weight was shown to be a significant covariate for apparent clearance (CL/F) and apparent volume of distribution (Vd/F). A double absorption peak of dDAVP lyophilisate in the first 2 hours post-administration was demonstrated.ConclusionsFor the first time, a double absorption profile of dDAVP lyophilisate was found in children, questioning extrapolation of bioequivalence from adults towards children. Moreover, the need for size-adapted dosing regimens of dDAVP lyophilisate in young children is indicated.Trial registration numberNTC02584231.

There is increasing attention given to the concept of trustworthiness for artificial intelligence and robotics. However, trust is highly context-dependent, varies among cultures, and requires reflection on others’ trustworthiness, appraising whether there is enough evidence to conclude that these agents deserve to be trusted. Moreover, little research exists on what happens when too much trust is placed in robots and autonomous systems. Conceptual clarity and a shared framework for approaching overtrust are missing. In this contribution, we offer an overview of pressing topics in the context of overtrust and robots and autonomous systems. Our review mobilizes insights solicited from in-depth conversations from a multidisciplinary workshop on the subject of trust in human–robot interaction (HRI), held at a leading robotics conference in 2020. A broad range of participants brought in their expertise, allowing the formulation of a forward-looking research agenda on overtrust and automation biases in robotics and autonomous systems. Key points include the need for multidisciplinary understandings that are situated in an eco-system perspective, the consideration of adjacent concepts such as deception and anthropomorphization, a connection to ongoing legal discussions through the topic of liability, and a socially embedded understanding of overtrust in education and literacy matters. The article integrates diverse literature and provides a ground for common understanding for overtrust in the context of HRI.

The authors investigated how eye movements are influenced by different reading goals in participants’ first (L1) and second language (L2). Participants read or studied the contents of texts while their eye movements were recorded. One group was asked to read L1 and L2 texts as they would read any expository text (informational reading). Another group was asked to study L1 and L2 texts for subsequent tests involving true/false questions (study condition). After reading, all participants, including those in the informational reading condition, completed the true/false tests without being able to further consult the texts, which allowed the authors to investigate the extent to which reading goal and text language affect recognition memory for texts. In general, more reading time was spent on studying than on informational reading, which also resulted in higher test scores in the study condition. The L2‐processing cost was larger in the study condition than in the informational reading condition: Participants needed approximately 20% more time to study L2 texts. The results of various eye movement measures suggest that this is caused by slower word recognition processes and a smaller amount of information that can be processed simultaneously in L2. This was true not only for the first reading of the text but also for the rereadings in the study condition. Interestingly, the additional time for L2 studying seemed to compensate for the less efficient processing, as the recognition test scores were the same in L2 as in L1.

ObjectiveThe prognostic importance of a coronary stenosis depends on its functional severity and its depending myocardial mass. Functional severity can be assessed by fractional flow reserve (FFR), estimated non-invasively by a specific validated CT algorithm (FFRCT). Calculation of myocardial mass at risk by that same set of CT data (CTmass), however, has not been prospectively validated so far. The aim of the present study was to compare relative territorial-based CTmass assessment with relative flow distribution, which is closely linked to true myocardial mass.MethodsIn this exploratory study, 35 patients with (near) normal coronary arteries underwent CT scanning for computed flow-based CTmass assessment and underwent invasive myocardial perfusion measurement in all 3 major coronary arteries by continuous thermodilution. Next, the mass and flows were calculated as relative percentages of total mass and perfusion.ResultsThe mean difference between CTmass per territory and invasively measured myocardial perfusion, both expressed as percentage of total mass and perfusion, was 5.3±6.2% for the left anterior descending territory, −2.0±7.4% for the left circumflex territory and −3.2±3.4% for the right coronary artery territory. The intraclass correlation between the two techniques was 0.90.ConclusionsOur study shows a close relationship between the relative mass of the perfusion territory calculated by the specific CT algorithm and invasively measured myocardial perfusion. As such, these data support the use of CTmass to estimate territorial myocardium-at-risk in proximal coronary arteries.

The Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) trial was a non-inferiority trial that compared percutaneous coronary intervention (PCI) using first-generation paclitaxel-eluting stents with coronary artery bypass grafting (CABG) in patients with de-novo three-vessel and left main coronary artery disease, and reported results up to 5 years. We now report 10-year all-cause death results.

Some previously described environmental associations for atopic eczema may be due to reverse causation. We explored the role of reverse causation by comparing individual- and school-level results for multiple atopic eczema risk factors. The International Study of Asthma and Allergies in Childhood (i.e, ISAAC) Phase Three surveyed children in schools (the sampling unit) regarding atopic eczema symptoms and potential risk factors. We assessed the effect of these risk factors on atopic eczema symptoms using mixed-effect logistic regression models, first with individual-level exposure data and second with school-level exposure prevalence. Overall, 546,348 children from 53 countries were included. At ages 6–7 years, the strongest individual-level associations were with current paracetamol use (odds ratio [OR] = 1.45, 95% confidence interval [CI] = 1.37–1.54), which persisted at school-level (OR = 1.55, 95% CI = 1.10–2.21), early-life antibiotics (OR = 1.41, 95% CI = 1.34–1.48), and early-life paracetamol use (OR = 1.28, 95% CI = 1.21–1.36), with the former persisting at the school level, whereas the latter was no longer observed (OR = 1.35, 95% CI = 1.00–1.82 and OR = 0.94, 95% CI = 0.69–1.28, respectively). At ages 13–14 years, the strongest associations at the individual level were with current paracetamol use (OR = 1.57, 95% CI = 1.51–1.63) and open-fire cooking (OR = 1.46, 95% CI = 1.33–1.62); both were stronger at the school level (OR = 2.57, 95% CI = 1.84–3.59 and OR = 2.38, 95% CI = 1.52–3.73, respectively). Association with exposure to heavy traffic (OR = 1.31, 95% CI = 1.27–1.36) also persisted at the school level (OR = 1.40, 95% CI = 1.07–1.82). Most individual- and school-level effects were consistent, tending to exclude reverse causation.

IMPORTANCE: Whether the improvement in myocardial perfusion provided by percutaneous coronary intervention (PCI) is associated with symptomatic relief or improved outcomes has not been well investigated. OBJECTIVE: To investigate the prognostic value of the improvement in fractional flow reserve (FFR) after PCI (ΔFFR) on patients’ symptoms and 2-year outcomes. DESIGN, SETTING, AND PARTICIPANTS: This study is a post hoc analysis of data from patients undergoing FFR-guided PCI in the randomized clinical trials Fractional Flow Reserve vs Angiography for Multivessel Evaluation (FAME) 1 (NCT00267774; 2009) and FAME 2 (NCT01132495; 2012), with inclusion of 2 years of follow-up data. The FAME 1 trial included patients with multivessel coronary artery disease from 20 medical centers in Europe and the United States. The FAME 2 trial included patients with stable coronary artery disease involving up to 3 vessels from 28 sites in Europe and North America. Lesions from the group in the FAME 1 trial from whom FFR was measured and the group in the FAME 2 trial who received FFR-guided PCI plus medical therapy were analyzed. Data analysis occurred from May 2017 to May 2018. INTERVENTIONS: Measure of post-PCI FFR. MAIN OUTCOMES AND MEASURES: Vessel-oriented clinical events at 2 years, a composite of cardiac death, target vessel-associated myocardial infarction, and target vessel revascularization. RESULTS: This analysis included 639 patients from whom pre-PCI and post-PCI FFR values were available. Of their 837 lesions, 277 were classified into the lowest tertile (ΔFFR≤0.18), 282 into the middle tertile (0.19≤ΔFFR≤0.31), and 278 into the highest tertile (ΔFFR>0.31). Vessel-oriented clinical events were significantly more frequent in the lowest tertile (n = 25 of 277 [9.1%]) compared with the highest tertile (n = 13 of 278 [4.7%]; hazard ratio, 2.01 [95% CI, 1.03-3.92]; P = .04). In addition, a significant association was observed between ΔFFR and symptomatic relief (odds ratio, 1.33 [95% CI, 1.02-1.74]; P = .02). CONCLUSIONS AND RELEVANCE: In this analysis of 2 randomized clinical trials, the larger the improvement in FFR, the larger the symptomatic relief and the lower the event rate. This suggests that measuring FFR before and after PCI provides clinically useful information.

Background: Selenium (Se) is a trace element active in selenoproteins, which can regulate oxidative stress. It is generally perceived as an import factor for maintaining health in the elderly. Methods: The goal of this review is to discuss selenium concentration in biological samples, primarily serum or plasma, as a function of age and its relation with longevity. The elemental level in various age-related diseases is reviewed. Conclusion: Highest selenium values were observed in healthy adults, while in an elderly population significantly lower concentrations were reported. Variables responsible for contradictory findings are mentioned. Risk and benefits of Se-supplementation still remain under debate.

The European Commission published two proposals that aim to adapt (tort) liability rules to the digital age, the circular economy and the impact of the global value chain. The ‘AI Liability Directive’ contains rules on the disclosure of information and the alleviation of the burden of proof in relation to damage caused by AI systems. The ‘revised Product Liability Directive’ substantially modifies the current product liability regime by broadening the scope, integrating new circumstances to assess the product's defectiveness and introducing provisions regarding presumptions of defectiveness and causation. In this article, we evaluate how both proposals provide some answers to major technological developments – in particular AI – in view of the issues they raise as identified in the legal literature. To do so, we also provide a clear understanding of the major provisions in both proposals, supported by visuals. Although we welcome both proposals for several reasons outlined in the article, different unclarities and inconsistencies need to be resolved. These inter alia relate to the unclarity of terms, the position of claimants, the uncertain interaction with other supranational initiatives and the many interpretation issues with regard to the fault-based liability regime. A more fundamental objection relates to the choice of the revised Product Liability Directive to capture all liability issues with AI systems, which comes at the cost of losing the connection to ‘product’ as a grounding concept. Our findings can be used by policymakers in further adapting and refining both proposals to the digital reality.

Optimization of quality of life (QOL) and minimization of long-term complications, particularly cardiovascular diseases are major outcome measures in liver transplant programs. This is particularly relevant in children. The authors describe lower physical fitness level, more deconditioning and lower HR-QOL in this group, emphasizing the importance of exercise stimulation and fitness programs. Supplemental digital content is available in the text.

Supplemental Digital Content is available in the text.

Self-driving cars are gradually being introduced in the United States and in several Member States of the European Union. Policymakers will thus have to make important choices regarding the application of the law. One important aspect relates to the question who should be held liable for the damage caused by such vehicles. Arguably, product liability schemes will gain importance considering that the driver's fault as a cause of damage will become less likely with the increase of autonomous systems. The application of existing product liability legislation, however, is not always straightforward. Without a proper and effective liability framework, other legal or policy initiatives concerning technical and safety matters related to self-driving cars might be in vain. The article illustrates this conclusion by analysing the limitation periods for filing a claim included in the European Union Product Liability Directive, which are inherently incompatible with the concept of autonomous vehicles. On a micro-level, we argue that every aspect of the Directive should be carefully considered in the light of the autonomisation of our society. On the macro-level, we believe that ongoing technological evolutions might be the perfect moment to bring the European Union closer to its citizens.

In humans, receptor-interacting protein kinase 4 (RIPK4) mutations can lead to the autosomal recessive Bartsocas-Papas and popliteal pterygium syndromes, which are characterized by severe skin defects, pterygia, as well as clefting. We show here that the epithelial fusions observed in RIPK4 full knockout (KO) mice are E-cadherin dependent, as keratinocyte-specific deletion of E-cadherin in RIPK4 full KO mice rescued the tail-to-body fusion and fusion of oral epithelia. To elucidate RIPK4 function in epidermal differentiation and development, we generated epidermis-specific RIPK4 KO mice (RIPK4EKO). In contrast to RIPK4 full KO epidermis, RIPK4EKOepidermis was normally stratified and the outside-in skin barrier in RIPK4EKOmice was largely intact at the trunk, in contrast to the skin covering the head and the outer end of the extremities. However, RIPK4EKOmice die shortly after birth due to excessive water loss because of loss of tight junction protein claudin-1 localization at the cell membrane, which results in tight junction leakiness. In contrast, mice with keratinocyte-specific RIPK4 deletion during adult life remain viable. Furthermore, our data indicate that epidermis-specific deletion of RIPK4 results in delayed keratinization and stratum corneum maturation and altered lipid organization and is thus indispensable during embryonic development for the formation of a functional inside-out epidermal barrier.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Proton pump inhibitor (PPI) use is becoming increasingly common. Although the toxicity profiles of PPIs are not well understood particularly in children, PPIs have been associated with increased risks of gastrointestinal and respiratory tract infection, vitamin B12deficiency, hypomagnesaemia, bone fractures, and rebound hyperacidity after discontinuation. Prescribers should take into account that PPI uses pose toxicity risks, which remain to be fully characterised in infants and children.