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Background: In patients with transposition of the great arteries and an arterial switch operation (TGA-ASO) right ventricular outflow tract (RVOT) obstruction is a common complication requiring one or more RVOT interventions., Objectives: We aimed to assess cardiopulmonary exercise capacity and right ventricular function in patients stratified for type of RVOT intervention., Methods: TGA-ASO patients (≥16 years) were stratified by type of RVOT intervention. The following outcome parameters were included: predicted (%) peak oxygen uptake (peak VO2), tricuspid annular plane systolic excursion (TAPSE), tricuspid Lateral Annular Systolic Velocity (TV S'), right ventricle (RV)-arterial coupling (defined as TAPSE/RV systolic pressure ratio), and N-terminal proBNP (NT-proBNP)., Results: 447 TGA patients with a mean age of 25.0 (interquartile range (IQR) 21-29) years were included. Patients without previous RVOT intervention (n = 338, 76%) had a significantly higher predicted peak VO2 (78.0 ± 17.4%) compared to patients with single approach catheter-based RVOT intervention (73.7 ± 12.7%), single approach surgical RVOT intervention (73.8 ± 28.1%), and patients with multiple approach RVOT intervention (66.2 ± 14.0%, p = 0.021). RV-arterial coupling was found to be significantly lower in patients with prior catheter-based and/or surgical RVOT intervention compared to patients without any RVOT intervention (p = 0.029)., Conclusions: TGA patients after a successful arterial switch repair have a decreased exercise capacity. A considerable amount of TGA patients with either catheter or surgical RVOT intervention perform significantly worse compared to patients without RVOT interventions., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Intestinal inflammation with contradictory data on faecal calprotectin (fCP) levels is documented in patients with cystic fibrosis (CF). The aim of this study was to longitudinally evaluate fCP in a cohort of children with CF and their relationship with clinical variables., Design: Prospective observational study to assess evolution of fCP levels, primary aimed at improving fat absorption. Along 1.5 years of follow-up (November 2016-May 2018) with four study visits pertaining to a pilot study (two of four) and to a clinical trial (two of four), the study outcomes were measured., Setting: Six European CF centres in the context of MyCyFAPP Project., Subjects: Children with CF and pancreatic insufficiency (2-18 years old)., Main Outcome Measurements: fCP levels, pulmonary function (percentage of forced expiratory volume in 1 s (FEV 1 %)) and coefficient of fat absorption (CFA). Additionally, in the last two visits, gastrointestinal (GI) symptoms were evaluated through the PedsQL-GI Questionnaire. Linear mixed regression models were applied to assess association between fCP and FEV 1 , CFA and GI symptoms., Results: Twenty-nine children with CF and pancreatic insufficiency were included. fCP levels were inversely associated with total modified specific PedsQL-GI score (p=0.04) and positively associated with diarrhoea (p=0.03), but not with CFA. Along the four study visits, fCP significantly increased (from 62 to 256 µg/g) and pulmonary function decreased (from 97% to 87%), with a significant inverse association between the two study outcomes (p<0.001)., Conclusions: In children with CF, fCP levels are inversely associated with pulmonary function and thus the specificity of fCP as a marker of intestinal inflammation in paediatric patients with CF warrants further investigation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

We have detected two mutations in the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at amino acid positions 1163 and 1167 that appeared independently in multiple transmission clusters and different genetic backgrounds. Furthermore, both mutations appeared together in a cluster of 1,627 sequences belonging to clade 20E. This cluster is characterized by 12 additional single nucleotide polymorphisms but no deletions. The available structural information on the S protein in the pre- and postfusion conformations predicts that both mutations confer rigidity, which could potentially decrease viral fitness. Accordingly, we observed reduced infectivity of this spike genotype relative to the ancestral 20E sequence in vitro , and the levels of viral RNA in nasopharyngeal swabs were not significantly higher. Furthermore, the mutations did not impact thermal stability or antibody neutralization by sera from vaccinated individuals but moderately reduce neutralization by convalescent-phase sera from the early stages of the pandemic. Despite multiple successful appearances of the two spike mutations during the first year of SARS-CoV-2 evolution, the genotype with both mutations was displaced upon the expansion of the 20I (Alpha) variant. The midterm fate of the genotype investigated was consistent with the lack of advantage observed in the clinical and experimental data. IMPORTANCE We observed repeated, independent emergence of mutations in the SARS-CoV-2 spike involving amino acids 1163 and 1167, within the HR2 functional motif. Conclusions derived from evolutionary and genomic diversity analysis suggest that the co-occurrence of both mutations might pose an advantage for the virus and therefore a threat to effective control of the epidemic. However, biological characterization, including in vitro experiments and analysis of clinical data, indicated no clear benefit in terms of stability or infectivity. In agreement with this, continuous epidemiological surveillance conducted months after the first observations revealed that both mutations did not successfully outcompete other variants and stopped circulating 9 months after their initial detection. Additionally, we evaluated the potential of both mutations to escape neutralizing antibodies, finding that the presence of these two mutations on their own is not likely to confer antibody escape. Our results provide an example of how newly emerged spike mutations can be assessed to better understand the risk posed by new variants and indicate that some spike mutations confer no clear advantage to the virus despite independently emerging multiple times and are eventually displaced by fitter variants.

Background: Despite advances in the first-line treatment of metastatic renal cell carcinoma (RCC), there is an unmet need for options to address disease progression during or after treatment with immune checkpoint inhibitors (ICIs). Pembrolizumab and lenvatinib are active as monotherapies in RCC; thus, we aimed to evaluate the combination of lenvatinib plus pembrolizumab in these patients., Methods: We report results of the metastatic RCC cohort from an open-label phase 1b/2 study of lenvatinib plus pembrolizumab in patients aged at least 18 years with selected solid tumours and an Eastern Cooperative Oncology Group performance status of 0-1. Oral lenvatinib at 20 mg was given once daily along with intravenous pembrolizumab at 200 mg once every 3 weeks. Patients remained on study drug treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent. Efficacy was analysed in patients with clear cell metastatic RCC receiving study drug by previous therapy grouping: treatment naive, previously treated ICI naive (previously treated with at least one line of therapy but not with an anti-PD-1 or anti-PD-L1 ICI), and ICI pretreated (ie, anti-PD-1 or anti-PD-L1) patients. Safety was analysed in all enrolled and treated patients. The primary endpoint was the objective response rate at week 24 per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) by investigator assessment. This trial is registered with ClinicalTrials.gov (NCT02501096) and with the EU Clinical Trials Register (EudraCT2017-000300-26), and is closed to new participants., Findings: Between July 21, 2015, and Oct 16, 2019, 145 patients were enrolled in the study. Two patients had non-clear cell RCC and were excluded from the efficacy analysis (one in the treatment-naive group and one in the ICI-pretreated group); thus, the population evaluated for efficacy comprised 143 patients (n=22 in the treatment-naive group, n=17 in the previously treated ICI-naive group, and n=104 in the ICI-pretreated group). All 145 enrolled patients were included in the safety analysis. The median follow-up was 19·8 months (IQR 14·3-28·4). The number of patients with an objective response at week 24 by irRECIST was 16 (72·7%, 95% CI 49·8-89·3) of 22 treatment-naive patients, seven (41·2%, 18·4-67·1) of 17 previously treated ICI-naive patients, and 58 (55·8%, 45·7-65·5) of 104 ICI-pretreated patients. Of 145 patients, 82 (57%) had grade 3 treatment-related adverse events and ten (7%) had grade 4 treatment-related adverse events. The most common grade 3 treatment-related adverse event was hypertension (30 [21%] of 145 patients). Treatment-related serious adverse events occurred in 36 (25%) patients, and there were three treatment-related deaths (upper gastrointestinal haemorrhage, sudden death, and pneumonia)., Interpretation: Lenvatinib plus pembrolizumab showed encouraging antitumour activity and a manageable safety profile and might be an option for post-ICI treatment of metastatic RCC., Funding: Eisai and Merck Sharp & Dohme., Competing Interests: Declaration of interests C-HL received support for this Article from Eisai and Merck; grants or contracts to their institution from Eisai and Merck; consulting fees from Eisai and Merck; for attending meetings and travel from Eisai; and fees for participation in a scientific advisory committee for Merck; consulting fees from Amgen, Bristol Myers Squibb, Exelixis, Pfizer, and EMD Serono; honoraria from AiCME, Intellisphere, and Research to Practice; research funds to the institute from Bristol Myers Squibb, Calithera, Eisai, Eli Lilly, Exelixis, Merck, and Pfizer. AYS participated on an advisory board for Eisai, Exelixis, Pfizer, and Roche; and received research funding from Bristol Myers Squibb, Eisai, and EMD Serono. DR received support for this Article from Eisai. AR received grants or contracts to their institution from Eisai and Merck; consulting fees to their institution from Eli Lilly; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bayer, Cardinal Health, Eli Lilly, and Sanofi; and research funding to their institution from Clovis Oncology, Eli Lilly, Pfizer/Astellas, and Seattle Genetics/Astellas. MHT received clinical research funding for the present work to their institution from Eisai; and honoraria for participation in advisory boards and speakers' bureaus from Eisai. JJH received grants or contracts from Merck; consulting fees from BostonGene and Eisai; support for attending meetings or travel, or both from Elsevier; and stock or stock options from BostonGene. AP received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Ipsen, and Pfizer; and support for attending meetings or travel, or both, from Bristol Myers Squibb and Pfizer. RGS received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Janssen, and Roche; support for attending meetings or travel, or both, from MSD-Merck and Pfizer; and participation on a data safety monitoring board or advisory board from Bristol Myers Squibb. ALC received consulting fees from Amgen; and payment for expert testimony from the Department of Justice. NJV received support for this Article, including provision of study patients, payments to institution, medical writing, and manuscript writing charges from Eisai and Merck; consulting fees from Eisai and Merck; and payment for legal testimony from Merck. MAB received grants or contracts to their institution from Advanced Accelerator Applications, a Novartis Company, AstraZeneca, Bayer, Bristol Myers Squibb, Genentech/Roche, Genome & Company, Incyte, Nektar, Peloton Therapeutics, Pfizer, Seattle Genetics, Tricon Pharmaceuticals, and Xencor; honoraria for participation in a data safety monitoring board or advisory board for AstraZeneca, Bayer, Bristol Myers Squibb, Calithera Biosciences, Eisai, Exelixis, Genomic Health, Janssen, Nektar, Pfizer, and Sanofi. ØKT received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from Astellas and Bristol Myers Squibb; and fees for participation on a data safety monitoring board or advisory board for Bayer. RFS received grants or contracts to their institution from AbbVie, Aduro, Bayer, Bristol Myers Squibb, CytomX, Eisai, Eli Lilly, Genentech/Roche, Immunocore, Merck, Mirati, Moderna, Novartis, and QED therapeutics; consulting fees from Aduro, Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, Janssen, Mirati, Pfizer, Puma, and Seattle Genetics; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astellas, Bristol Myers Squibb, Eisai, Exelixis, Pfizer, and Seattle Genetics; support for attending meetings or travel, or both, from AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Mirati; and patents pending, PCT/US2020/031357 on neoantigens in cancer. DH received support for this Article to their institution from Eisai; consulting fees from Astellas, AstraZeneca, Bayer, Eisai, Ipsen, Janssen-Cilag, and Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Advanced Accelerator Applications, a Novartis Company, Astellas, Bayer, Bristol Myers Squibb, Ipsen, Janssen-Cilag, Novartis, and Sanofi; and participation on an advisory board for Astellas, AstraZeneca, Bayer, Eisai, Ipsen, Janssen-Cilag, and Roche; SJ has stock or stock options in Merck. EVS and RFP are employed by, and have stock or stock options in, Merck. JW and PK are employed by Eisai. CEO and ADS are employed by Eisai Europe. RJM received support for the present Article from Eisai and Merck; grants or contracts from Bristol Myers Squibb, Genentech, Novartis, Pfizer, and Roche; consulting fees from AstraZeneca, Aveo Pharmaceuticals, EMD Serono, Exelixis, Genentech, Incyte, Eli Lilly, Novartis, Pfizer, and Roche; and support for attending meetings or travel, or both, from Bristol Myers Squibb. CDS, DRS, SGR, MG, DR, and JC declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: The safety of Helicobacter pylori eradication treatments and to what extent adverse events (AEs) influence therapeutic compliance in clinical practice are hardly known. Our aim was to assess the frequency, type, intensity, and duration of AEs, and their impact on compliance, for the most frequently used treatments in the "European Registry on Helicobacter pylori management.", Methods: Systematic prospective noninterventional registry of the clinical practice of European gastroenterologists (27 countries, 300 investigators) on the management of H. pylori infection in routine clinical practice. All prescribed eradication treatments and their corresponding safety profile were recorded. AEs were classified depending on the intensity of symptoms as mild/moderate/severe and as serious AEs. All data were subject to quality control., Results: The different treatments prescribed to 22,492 patients caused at least 1 AE in 23% of the cases; the classic bismuth-based quadruple therapy was the worst tolerated (37% of AEs). Taste disturbance (7%), diarrhea (7%), nausea (6%), and abdominal pain (3%) were the most frequent AEs. The majority of AEs were mild (57%), 6% were severe, and only 0.08% were serious, with an average duration of 7 days. The treatment compliance rate was 97%. Only 1.3% of the patients discontinued treatment due to AEs. Longer treatment durations were significantly associated with a higher incidence of AEs in standard triple, concomitant, bismuth quadruple, and levofloxacin triple or quadruple therapies., Discussion: Helicobacter pylori eradication treatment frequently induces AEs, although they are usually mild and of limited duration. Their appearance does not interfere significantly with treatment compliance., Competing Interests: The remaining list of authors, their affiliations, contributions and conflicts of interests are listed in Supplementary file 1. Contribution Log, available online at http://links.lww.com/AJG/B961., (Copyright © 2021 by The American College of Gastroenterology.)

Aims and Objectives: The aim of the study was to compare advanced practice in epilepsy nurses in Spain and United Kingdom, identifying differences in the domains of standard advanced practice., Background: Europe has recently faced the challenge of providing high-quality care for patients with epilepsy, a disease that generates many health demands. In some countries, such as the United Kingdom, advanced practice nursing is well established and could serve as a guide for implantation in countries where it is still in development, as is the case of Spain., Design: A multicentre cross-sectional descriptive cohort study compared differences in the roles of advanced practice nurses in Spain and the United Kingdom., Methods: The Advanced Practice Role Delineation Tool and its validated Spanish version were administered using an online questionnaire in a cohort of advanced practice epilepsy nurses in both countries. A convenience sample was recruited between January to December 2019. The study complied with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist., Results: Most United Kingdom nurses in our sample came from community environments, in contrast to Spanish nurses who worked in hospital. All domains analysed in the survey had significantly higher scores in the United Kingdom than in the Spanish cohort, especially in the research and leadership domains., Conclusions: The advanced practice role in Spain is underdeveloped compared with the United Kingdom. Differences in the settings of advanced roles in epilepsy nurses may be explained by greater community practice in the United Kingdom and differences in organisational and health systems., Relevance to Clinical Practice: Our study showed the need to implement specific policies to develop advance practice nurse roles in Spain to improve the quality of care of patients with epilepsy., (© 2021 John Wiley & Sons Ltd.)

Background: The X-linked Danon disease manifests by severe cardiomyopathy, myopathy, and neuropsychiatric problems. We designed this registry to generate a comprehensive picture of clinical presentations and outcome of patients with Danon disease in cardiomyopathy centers throughout Europe., Methods: Clinical and genetic data were collected in 16 cardiology centers from 8 European countries., Results: The cohort comprised 30 male and 27 female patients. The age at diagnosis was birth to 42 years in men and 2 to 65 in women. Cardiac involvement was observed in 96%. Extracardiac manifestations were prominent in men but not in women. Left ventricular (LV) hypertrophy was reported in 73% of male and 74% of female patients. LV systolic dysfunction was reported in 40% of men (who had LV ejection fraction, 34±11%) and 59% of women (LV ejection fraction, 28±13%). The risk of arrhythmia and heart failure was comparable among sexes. The age of first heart failure hospitalization was lower in men (18±6 versus 28±17 years; P <0.003). Heart failure was the leading cause of death (10 of 17; 59%), and LV systolic dysfunction predicted an adverse outcome. Eight men and 8 women (28%) underwent heart transplantation or received an LV assist device. Our cohort suggests better prognosis of female compared with male heart transplant recipients., Conclusions: Danon disease presents earlier in men than in women and runs a malignant course in both sexes, due to cardiac complications. Cardiomyopathy features, heart failure and arrhythmia, are similar among the sexes. Clinical diagnosis and management is extremely challenging in women due to phenotypic diversity and the absence of extracardiac manifestations.

Although liver transplantation (LT) is the best treatment for patients with localized hepatocellular carcinoma (HCC), recurrence occurs in 6%-18% of patients. Several factors, particularly morphological criteria combined with dynamic parameters, known before LT modify this risk and combined in prediction models may be used to stratify patients at need of variable surveillance strategies. Additional variables though likely explain differences in recurrence rates in patients with the same pre-LT HCC status. One of these variables is possibly immunosuppression (IS). Once recurrence takes place, management is highly heterogenous. Within the International Liver Transplantation Society Consensus Conference on Liver Transplant Oncology, working group 4 aim was to analyze the data regarding posttransplant management of recipients undergoing LT for HCC. Three areas of research were considered: (1) cancer prediction models and surveillance strategies; (2) tailored IS for cancer recipients; and (3) new adjuvant therapies for HCC recurrence. Following formulation of several questions, a literature search was undertaken with abstract review followed by article retrieval and full-data extraction. The grading of recommendations assessment, development and evaluation (GRADE) system was used for evidence rating incorporating strength of recommendation and quality of evidence.

Introduction and Objectives: We describe the results for Spain of the Second European Cardiac Resynchronization Therapy Survey (CRT-Survey II) and compare them with those of the other participating countries., Methods: We included patients undergoing CRT device implantation between October 2015 and December 2016 in 36 participating Spanish centers. We registered the patients' baseline characteristics, implant procedure data, and short-term follow-up information until hospital discharge., Results: Implant success was achieved in 95.9%. The median [interquartile range] annual implantation rate by center was significantly lower in Spain than in the other participating countries: 30 implants/y [21-50] vs 55 implants/y [33-100]; P=.00003. In Spanish centers, there was a lower proportion of patients ≥ 75 years (27.9% vs 32.4%; P=.0071), a higher proportion in New York Heart Association functional class II (46.9% vs 36.9%; P <.00001), and a higher percentage with electrocardiographic criteria of left bundle branch block (82.9% vs 74.6%; P <.00001). The mean length of hospital stay was significantly lower in Spanish centers (5.8±8.5 days vs 6.4±11.6; P <.00001). Spanish patients were more likely to receive a quadripolar LV lead (74% vs 56%; P <.00001) and to be followed up by remote monitoring (55.8% vs 27.7%; P <.00001)., Conclusions: The CRT-Survey II shows that, compared with other participating countries, fewer patients in Spain aged ≥ 75 years received a CRT device, while more patients were in New York Heart Association functional class II and had left bundle branch block. In addition, the length of hospital stay was shorter, and there was greater use of quadripolar LV leads and remote CRT monitoring., (Copyright © 2018 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Aims: Female sex is considered an independent risk factor of transvenous leads extraction (TLE) procedure. The aim of the study was to evaluate the effectiveness of TLE in women compared with men., Methods and Results: A post hoc analysis of risk factors and effectiveness of TLE in women and men included in the ESC-EHRA EORP ELECTRa registry was conducted. The rate of major complications was 1.96% in women vs. 0.71% in men; P = 0.0025. The number of leads was higher in men (mean 1.89 vs. 1.71; P < 0.0001) with higher number of abandoned leads in women (46.04% vs. 34.82%; P < 0.0001). Risk factors of TLE differed between the sexes, of which the major were: signs and symptoms of venous occlusion [odds ratio (OR) 3.730, confidence interval (CI) 1.401-9.934; P = 0.0084], cumulative leads dwell time (OR 1.044, CI 1.024-1.065; P < 0.001), number of generator replacements (OR 1.029, CI 1.005-1.054; P = 0.0184) in females and the number of leads (OR 6.053, CI 2.422-15.129; P = 0.0001), use of powered sheaths (OR 2.742, CI 1.404-5.355; P = 0.0031), and white blood cell count (OR 1.138, CI 1.069-1.212; P < 0.001) in males. Individual radiological and clinical success of TLE was 96.29% and 98.14% in women compared with 98.03% and 99.21% in men (P = 0.0046 and 0.0098)., Conclusion: The efficacy of TLE was lower in females than males, with a higher rate of periprocedural major complications. The reasons for this difference are probably related to disparities in risk factors in women, including more pronounced leads adherence to the walls of the veins and myocardium. Lead management may be key to the effectiveness of TLE in females., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Objectives: This study sought to compare sex difference for procedural aspects and complications in the European Society of Cardiology CRT Survey II, exploring whether adverse events were related to the type of CRT device implanted., Background: Sex-related differences in procedural aspects and complications in patients undergoing cardiac resynchronization therapy (CRT) implantation has not been explored in a real-life population., Methods: A post-hoc analysis of procedural data and complications in different sexes and factors associated with events was performed from data collected in the European Society of Cardiology CRT Survey II., Results: Of all patients (n = 11,088) included, 24.3% were women. The mean age (70 years of age) of male and female recipients was similar. Female patients more frequently had an idiopathic cardiomyopathy (67.4% vs. 44.1%) and fewer comorbidities, including atrial fibrillation (34.8% vs. 42.8%), diabetes (29.1% vs. 32.1%), chronic obstructive lung disease (10.3% vs. 12.6%), and renal failure (28.7% vs. 31.9%), compared with men. More women compared with men had a pacemaker (56.6% vs. 46.3%) and much less often an implantable cardioverter-defibrillator (CRT-D) (19.0% vs. 34.7%) implant. Periprocedural event rate was the highest in women with CRT with defibrillator (7.1% vs. 4.8% in men), followed by women with a CRT with pacing (5.5% vs. 4.4% in men). The higher periprocedural event rate in CRT-D women was attributable primarily to the occurrence of pneumothorax (1.4%), coronary sinus dissection (2.1%), and pericardial tamponade (0.3%). The rate of in-hospital major adverse events (6.0%) and complications necessitating reoperation (4.0%) was not different among sex and device type., Conclusions: Women are more likely to experience adverse procedure-related events during CRT implantation. Thus, preventive strategies should be employed to minimize complication rate., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: To date, there are no data from randomized controlled studies on the benefit of cardiac resynchronization therapy (CRT) when implanted as an upgrade in patients with a previous device as compared to de novo CRT. In the CRT Survey II we compared the baseline data of patients upgraded to CRT (CRT-P/CRT-D) from a previous pacemaker (PM) or implantable cardioverter-defibrillator (ICD) to de novo CRT implantation., Methods and Results: In the European CRT Survey II, clinical practice data of patients undergoing CRT and/or ICD implantation across 42 European Society of Cardiology (ESC) countries were collected between October 2015 and December 2016. Out of a total of 11 088 patients, 2396 (23.2%) were upgraded from a previous PM or ICD and 7933 (76.8%) underwent de novo implantation. Compared to de novo implantations, upgraded patients were older, more often male, more frequently had ischaemic heart failure aetiology, atrial fibrillation, reduced renal function, worse heart failure symptoms, and higher N-terminal pro-B-type natriuretic peptide levels. Upgraded patients were more often PM-dependent and less frequently received CRT-D. Total peri-procedural, in-hospital complications and length of hospital stay were similar. Upgraded patients were less frequently treated with heart failure medication at discharge., Conclusion: Despite a lack of evidenced-based data, close to one quarter of all CRT implantations across 42 ESC countries were upgrades from a previous PM or ICD. Despite older age and worse symptoms, the CRT implantation procedures in upgraded patients were equally frequently successful and complications similar to de novo implantations. These results call for more studies., (© 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.)

Purpose: To analyze the presence of total IgA and anti-gliadin antibodies (AGA) in BM from CD mothers who follow a gluten-free diet (GFD) and from mothers on a normal gluten-containing diet (ND)., Methods: 218 samples of mature milk were obtained at different months of lactation (1-6) from 83 mothers (2 or more samples per mother) from Italy (Naples), The Netherlands (Leiden) and Spain (Madrid, Valencia and Reus): 42 CD mothers on GFD for more than 2 years and 41 non-CD mothers on a ND. Whey samples were analyzed for AGA-IgA by an indirect homemade ELISA and for total IgA (g/L) by a commercial ELISA kit., Results: AGA-IgA was detected in BM, both in mothers on a GFD and mothers on a ND. AGA-IgA levels in both groups of mothers, CD and non-CD, show the same trend towards decreasing slightly along the months of lactation (p = 0.91). A different trend is observed for total IgA levels, decreasing markedly in CD mothers from the first month of lactation onwards but remaining stable in non-CD mothers (p = 0.048). A statistically significant association was found between the means of total IgA and AGA-IgA (p < 0.001)., Conclusion: AGA-IgA is present in BM from mothers on a ND as well as in BM from mothers who had been on a GFD for years. This reflects the existence of a long-lasting immunological memory independent of the mother's diet. If the presence of these antibodies has any role in promoting the acquisition of gluten tolerance in the infant, our study shows that children of CD mothers would be on equal conditions as children of non-CD mothers.

The European Society for Medical Oncology (ESMO) consensus conference on testicular cancer was held on 3-5 November 2016 in Paris, France. The conference included a multidisciplinary panel of 36 leading experts in the diagnosis and treatment of testicular cancer (34 panel members attended the conference; an additional two panel members [CB and K-PD] participated in all preparatory work and subsequent manuscript development). The aim of the conference was to develop detailed recommendations on topics relating to testicular cancer that are not covered in detail in the current ESMO Clinical Practice Guidelines (CPGs) and where the available level of evidence is insufficient. The main topics identified for discussion related to: (1) diagnostic work-up and patient assessment; (2) stage I disease; (3) stage II-III disease; (4) post-chemotherapy surgery, salvage chemotherapy, salvage and desperation surgery and special topics; and (5) survivorship and follow-up schemes. The experts addressed questions relating to one of the five topics within five working groups. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel. A consensus vote was obtained following whole-panel discussions, and the consensus recommendations were then further developed in post-meeting discussions in written form. This manuscript presents the results of the expert panel discussions, including the consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.

Background: Cardiac resynchronisation therapy (CRT) reduces morbidity and mortality in appropriately selected patients with heart failure and is strongly recommended for such patients by guidelines. A European Society of Cardiology (ESC) CRT survey conducted in 2008-2009 showed considerable variation in guideline adherence and large individual, national and regional differences in patient selection, implantation practice and follow-up. Accordingly, two ESC associations, the European Heart Rhythm Association and the Heart Failure Association, designed a second prospective survey to describe contemporary clinical practice regarding CRT., Methods and Results: A survey of the clinical practice of CRT-P and CRT-D implantation was conducted from October 2015 to December 2016 in 42 ESC member countries. Implanting centres provided information about their hospital and CRT service and were asked to complete a web-based case report form collecting information on patient characteristics, investigations, implantation procedures and complications during the index hospitalisation. The 11 088 patients enrolled represented 11% of the total number of expected implantations in participating countries during the survey period; 32% of patients were aged ≥75 years, 28% of procedures were upgrades from a permanent pacemaker or implantable cardioverter-defibrillator and 30% were CRT-P rather than CRT-D. Most patients (88%) had a QRS duration ≥130 ms, 73% had left bundle branch block and 26% were in atrial fibrillation at the time of implantation. Large geographical variations in clinical practice were observed., Conclusion: CRT Survey II provides a valuable source of information on contemporary clinical practice with respect to CRT implantation in a large sample of ESC member states. The survey permits assessment of guideline adherence and demonstrates variations in patient selection, management, implantation procedure and follow-up strategy., (© 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.)

Background: In neuroblastoma (NB), the most powerful prognostic marker, the MYCN amplification (MNA), occasionally shows intratumoural heterogeneity (ITH), i.e. coexistence of MYCN-amplified and non-MYCN-amplified tumour cell clones, called heterogeneous MNA (hetMNA). Prognostication and therapy allocation are still unsolved issues., Methods: The SIOPEN Biology group analysed 99 hetMNA NBs focussing on the prognostic significance of MYCN ITH., Results: Patients <18 months (18 m) showed a better outcome in all stages as compared to older patients (5-year OS in localised stages: <18 m: 0.95 ± 0.04, >18 m: 0.67 ± 0.14, p = 0.011; metastatic: <18 m: 0.76 ± 0.15, >18 m: 0.28 ± 0.09, p = 0.084). The genomic 'background', but not MNA clone sizes, correlated significantly with relapse frequency and OS. No relapses occurred in cases of only numerical chromosomal aberrations. Infiltrated bone marrows and relapse tumour cells mostly displayed no MNA. However, one stage 4s tumour with segmental chromosomal aberrations showed a homogeneous MNA in the relapse., Conclusions: This study provides a rationale for the necessary distinction between heterogeneous and homogeneous MNA. HetMNA tumours have to be evaluated individually, taking age, stage and, most importantly, genomic background into account to avoid unnecessary upgrading of risk/overtreatment, especially in infants, as well as in order to identify tumours prone to developing homogeneous MNA.

: The indications for the use of an inferior vena cava filter (IVCF) in the context of deep venous thrombosis to prevent pulmonary embolism remain controversial. Despite wide use in clinical practice, great variation exists in national and international guidelines in regard to the indications. In addition, clinical practice is based on poor-quality data from trauma and bariatric surgery with a high incidence of complications. It is often difficult to assess their efficacy and lack of filter retrieval appears to be a substantial issue compared with a potential benefit by insertion of these devices. Complications usually refer to increased risk of deep venous thrombosis, filter perforation, filter penetration, filter migration, inferior vena cava occlusion and subsequently failure in pulmonary embolism prevention. Evidence from low-quality studies or registries, with small numbers of patients and conflicting findings, does not allow for a strong recommendation for or against the use of IVCFs. IVCFs should only be considered in cases of very high risk of pulmonary embolism and in perioperative situations at very high risk of bleeding, resulting in a prolonged contra-indication to pharmacological prophylaxis.

: Although there are numerous publications addressing venous thromboembolism and its prevention in neurosurgery, there are relatively few high-quality studies to guide decisions regarding thromboprophylaxis. In patients undergoing craniotomy, we recommend that if intermittent pneumatic compression (IPC) is used, it should be applied before the surgical procedure or on admission (Grade 1C). In craniotomy patients at particularly high risk for venous thromboembolism, we suggest considering the initiation of mechanical thromboprophylaxis with IPC preoperatively with addition of low molecular weight heparin (LMWH) postoperatively when the risk of bleeding is presumed to be decreased (Grade 2C). In patients with non-traumatic intracranial haemorrhage, we suggest thromboprophylaxis with IPC (Grade 2C). For patients who have had non-traumatic intracranial haemorrhage, we suggest giving consideration to commencement of LMWH or low-dose unfractionated heparin when the risk of bleeding is presumed to be low (Grade 2C). We suggest continuing thromboprophylaxis until full mobilisation of the patient (Grade 2C). For patients undergoing spinal surgery with no additional risk factors, we suggest no active thromboprophylaxis intervention apart from early mobilisation (Grade 2C). For patients undergoing spinal surgery with additional risk factors, we recommend starting mechanical thromboprophylaxis with IPC (Grade 1C), and we suggest the addition of LMWH postoperatively when the risk of bleeding is presumed to be decreased (Grade 2C).