Showing papers by "Autonomous University of Barcelona published in 2018"

Graph Attention Networks

Abstract: We present graph attention networks (GATs), novel neural network architectures that operate on graph-structured data, leveraging masked self-attentional layers to address the shortcomings of prior methods based on graph convolutions or their approximations. By stacking layers in which nodes are able to attend over their neighborhoods' features, we enable (implicitly) specifying different weights to different nodes in a neighborhood, without requiring any kind of costly matrix operation (such as inversion) or depending on knowing the graph structure upfront. In this way, we address several key challenges of spectral-based graph neural networks simultaneously, and make our model readily applicable to inductive as well as transductive problems. Our GAT models have achieved or matched state-of-the-art results across four established transductive and inductive graph benchmarks: the Cora, Citeseer and Pubmed citation network datasets, as well as a protein-protein interaction dataset (wherein test graphs remain unseen during training).

Minimal information for studies of extracellular vesicles 2018 (MISEV2018) : a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

Abstract: The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.

Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer

Abstract: Background First-line therapy for advanced non–small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial. Methods In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy...

Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct.

Abstract: BackgroundThe effect of endovascular thrombectomy that is performed more than 6 hours after the onset of ischemic stroke is uncertain. Patients with a clinical deficit that is disproportionately severe relative to the infarct volume may benefit from late thrombectomy. MethodsWe enrolled patients with occlusion of the intracranial internal carotid artery or proximal middle cerebral artery who had last been known to be well 6 to 24 hours earlier and who had a mismatch between the severity of the clinical deficit and the infarct volume, with mismatch criteria defined according to age (<80 years or ≥80 years). Patients were randomly assigned to thrombectomy plus standard care (the thrombectomy group) or to standard care alone (the control group). The coprimary end points were the mean score for disability on the utility-weighted modified Rankin scale (which ranges from 0 [death] to 10 [no symptoms or disability]) and the rate of functional independence (a score of 0, 1, or 2 on the modified Rankin scale, whic...

Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer

Abstract: Background Most women with newly diagnosed advanced ovarian cancer have a relapse within 3 years after standard treatment with surgery and platinum-based chemotherapy. The benefit of the o...

Analysis of shared heritability in common disorders of the brain

Abstract: Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Identifying the Best Machine Learning Algorithms for Brain Tumor Segmentation, Progression Assessment, and Overall Survival Prediction in the BRATS Challenge

Abstract: Gliomas are the most common primary brain malignancies, with different degrees of aggressiveness, variable prognosis and various heterogeneous histologic sub-regions, i.e., peritumoral edematous/invaded tissue, necrotic core, active and non-enhancing core. This intrinsic heterogeneity is also portrayed in their radio-phenotype, as their sub-regions are depicted by varying intensity profiles disseminated across multi-parametric magnetic resonance imaging (mpMRI) scans, reflecting varying biological properties. Their heterogeneous shape, extent, and location are some of the factors that make these tumors difficult to resect, and in some cases inoperable. The amount of resected tumoris a factor also considered in longitudinal scans, when evaluating the apparent tumor for potential diagnosis of progression. Furthermore, there is mounting evidence that accurate segmentation of the various tumor sub-regions can offer the basis for quantitative image analysis towards prediction of patient overall survival. This study assesses thestate-of-the-art machine learning (ML) methods used for brain tumor image analysis in mpMRI scans, during the last seven instances of the International Brain Tumor Segmentation (BraTS) challenge, i.e., 2012-2018. Specifically, we focus on i) evaluating segmentations of the various glioma sub-regions in pre-operative mpMRI scans, ii) assessing potential tumor progression by virtue of longitudinal growth of tumor sub-regions, beyond use of the RECIST/RANO criteria, and iii) predicting the overall survival from pre-operative mpMRI scans of patients that underwent gross tota lresection. Finally, we investigate the challenge of identifying the best ML algorithms for each of these tasks, considering that apart from being diverse on each instance of the challenge, the multi-institutional mpMRI BraTS dataset has also been a continuously evolving/growing dataset.

Neurofilaments as biomarkers in neurological disorders

Abstract: Neuroaxonal damage is the pathological substrate of permanent disability in various neurological disorders. Reliable quantification and longitudinal follow-up of such damage are important for assessing disease activity, monitoring treatment responses, facilitating treatment development and determining prognosis. The neurofilament proteins have promise in this context because their levels rise upon neuroaxonal damage not only in the cerebrospinal fluid (CSF) but also in blood, and they indicate neuroaxonal injury independent of causal pathways. First-generation (immunoblot) and second-generation (enzyme-linked immunosorbent assay) neurofilament assays had limited sensitivity. Third-generation (electrochemiluminescence) and particularly fourth-generation (single-molecule array) assays enable the reliable measurement of neurofilaments throughout the range of concentrations found in blood samples. This technological advancement has paved the way to investigate neurofilaments in a range of neurological disorders. Here, we review what is known about the structure and function of neurofilaments, discuss analytical aspects and knowledge of age-dependent normal ranges of neurofilaments and provide a comprehensive overview of studies on neurofilament light chain as a marker of axonal injury in different neurological disorders, including multiple sclerosis, neurodegenerative dementia, stroke, traumatic brain injury, amyotrophic lateral sclerosis and Parkinson disease. We also consider work needed to explore the value of this axonal damage marker in managing neurological diseases in daily practice.

PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma

Abstract: Background No systemic therapies have been approved for the treatment of advanced cutaneous squamous-cell carcinoma. This cancer may be responsive to immune therapy, because the mutation burden of the tumor is high and the disease risk is strongly associated with immunosuppression. In the dose-escalation portion of the phase 1 study of cemiplimab, a deep and durable response was observed in a patient with metastatic cutaneous squamous-cell carcinoma. Methods We report the results of the phase 1 study of cemiplimab for expansion cohorts of patients with locally advanced or metastatic cutaneous squamous-cell carcinoma, as well as the results of the pivotal phase 2 study for a cohort of patients with metastatic disease (metastatic-disease cohort). In both studies, the patients received an intravenous dose of cemiplimab (3 mg per kilogram of body weight) every 2 weeks and were assessed for a response every 8 weeks. In the phase 2 study, the primary end point was the response rate, as assessed by independent central review. Results In the expansion cohorts of the phase 1 study, a response to cemiplimab was observed in 13 of 26 patients (50%; 95% confidence interval [CI], 30 to 70). In the metastatic-disease cohort of the phase 2 study, a response was observed in 28 of 59 patients (47%; 95% CI, 34 to 61). The median follow-up was 7.9 months in the metastatic-disease cohort of the phase 2 study. Among the 28 patients who had a response, the duration of response exceeded 6 months in 57%, and 82% continued to have a response and to receive cemiplimab at the time of data cutoff. Adverse events that occurred in at least 15% of the patients in the metastatic-disease cohort of the phase 2 study were diarrhea, fatigue, nausea, constipation, and rash; 7% of the patients discontinued treatment because of an adverse event. Conclusions Among patients with advanced cutaneous squamous-cell carcinoma, cemiplimab induced a response in approximately half the patients and was associated with adverse events that usually occur with immune checkpoint inhibitors. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT02383212 and NCT02760498 .).

Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma

Abstract: We describe results from IMmotion150, a randomized phase 2 study of atezolizumab (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in 305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+ populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69–1.45) and 1.19 (95% CI, 0.82–1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38–1.08) and 1.03 (95% CI, 0.63–1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN-γ response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments. These molecular profiles suggest that prediction of outcomes with anti-VEGF and immunotherapy may be possible and offer mechanistic insights into how blocking VEGF may overcome resistance to immune checkpoint blockade. An exploratory randomized controlled clinical trial of renal cell carcinoma identifies molecular patterns distinguishing responders to immune checkpoint blockade alone or combined with angiogenesis inhibitor versus angiogenesis inhibitor alone.

The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria.

Abstract: This evidence- and consensus-based guideline was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. The conference was held on 1 December 2016. It is a joint initiative of the Dermatology Sectionof the European Academy of Allergology and Clinical Immunology (EAACI), the EU-founded network of excellence, the Global Allergy and Asthma European Network (GA(2)LEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO) with the participation of 48 delegates of 42 national and international societies. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease, presenting with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic spontaneous urticaria and other chronic forms of urticaria are disabling, impair quality of life and affect performance at work and school. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria.

General data protection regulation

Abstract: Presentacio sobre l'Oficina de Proteccio de Dades Personals de la UAB i la politica Open Science. Va formar part de la conferencia "Les politiques d'Open Data / Open Acces: Implicacions a la recerca" orientada a investigadors i gestors de projectes europeus que va tenir lloc el 20 de setembre de 2018 a la Universitat Autonoma de Barcelona

Genetics of male infertility.

Abstract: Male infertility is a multifactorial pathological condition affecting approximately 7% of the male population. The genetic landscape of male infertility is highly complex as semen and testis histological phenotypes are extremely heterogeneous, and at least 2,000 genes are involved in spermatogenesis. The highest frequency of known genetic factors contributing to male infertility (25%) is in azoospermia, but the number of identified genetic anomalies in other semen and aetiological categories is constantly growing. Genetic screening is relevant for its diagnostic value, clinical decision making, and appropriate genetic counselling. Anomalies in sex chromosomes have major roles in severe spermatogenic impairment. Autosome-linked gene mutations are mainly involved in central hypogonadism, monomorphic teratozoospermia or asthenozoospermia, congenital obstructive azoospermia, and familial cases of quantitative spermatogenic disturbances. Results from whole-genome association studies suggest a marginal role for common variants as causative factors; however, some of these variants can be important for pharmacogenetic purposes. Results of studies on copy number variations (CNVs) demonstrate a considerably higher CNV load in infertile patients than in normozoospermic men, whereas whole-exome analysis has proved to be a highly successful diagnostic tool in familial cases of male infertility. Despite such efforts, the aetiology of infertility remains unknown in about 40% of patients, and the discovery of novel genetic factors in idiopathic infertility is a major challenge for the field of androgenetics. Large, international, and consortium-based whole-exome and whole-genome studies are the most promising approach for the discovery of the missing genetic aetiology of idiopathic male infertility.

The Beaker phenomenon and the genomic transformation of northwest Europe

Abstract: From around 2750 to 2500 bc, Bell Beaker pottery became widespread across western and central Europe, before it disappeared between 2200 and 1800 bc. The forces that propelled its expansion are a matter of long-standing debate, and there is support for both cultural diffusion and migration having a role in this process. Here we present genome-wide data from 400 Neolithic, Copper Age and Bronze Age Europeans, including 226 individuals associated with Beaker-complex artefacts. We detected limited genetic affinity between Beaker-complex-associated individuals from Iberia and central Europe, and thus exclude migration as an important mechanism of spread between these two regions. However, migration had a key role in the further dissemination of the Beaker complex. We document this phenomenon most clearly in Britain, where the spread of the Beaker complex introduced high levels of steppe-related ancestry and was associated with the replacement of approximately 90% of Britain's gene pool within a few hundred years, continuing the east-to-west expansion that had brought steppe-related ancestry into central and northern Europe over the previous centuries.

Multi-Ethnic Genome-wide Association Study for Atrial Fibrillation

Abstract: Atrial fibrillation (AF) affects more than 33 million individuals worldwide1 and has a complex heritability2. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

Epidemiology of atopic dermatitis in adults: Results from an international survey.

Abstract: Background There are gaps in our knowledge of the prevalence of adult atopic dermatitis (AD). Objective To estimate the prevalence of AD in adults and by disease severity. Methods This international, cross-sectional, web-based survey was performed in the United States, Canada, France, Germany, Italy, Spain, United Kingdom, and Japan. Adult members of online respondent panels were sent a questionnaire for AD identification and severity assessment; demographic quotas ensured population representativeness for each country. A diagnosis of AD required subjects to be positive on the modified UK Working Party/ISAAC criteria and self-report of ever having an AD diagnosis by a physician. The proportion of subjects with AD who reported being treated for their condition was determined and also used to estimate prevalence. Severity scales were Patient-Oriented SCORAD, Patient-Orientated Eczema Measure, and Patient Global Assessment. Results Among participants by region, the point prevalence of adult AD in the overall/treated populations was 4.9%/3.9% in the US, 3.5%/2.6% in Canada, 4.4%/3.5% in the EU, and 2.1%/1.5% in Japan. The prevalence was generally lower for males vs females, and decreased with age. Regional variability was observed within countries. Severity varied by scale and region; however, regardless of the scale or region, proportion of subjects reporting severe disease was lower than mild or moderate disease. Conclusions Prevalence of adult AD ranged from 2.1% to 4.9% across countries. Severe AD represented a small proportion of the overall AD population regardless of measure or region.

Patterns of New Physics in b → sℓ+ℓ− transitions in the light of recent data

Abstract: In the Standard Model (SM), the rare transitions where a bottom quark decays into a strange quark and a pair of light leptons exhibit a potential sensitivity to physics beyond the SM. In addition, the SM embeds Lepton Flavour Universality (LFU), leading to almost identical probabilities for muon and electron modes. The LHCb collaboration discovered a set of deviations from the SM expectations in decays to muons and also in ratios assessing LFU. Other experiments (Belle, ATLAS, CMS) found consistent measurements, albeit with large error bars. We perform a global fit to all available b → sl+l− data (l = e, μ) in a model-independent way allowing for different patterns of New Physics. For the first time, the NP hypothesis is preferred over the SM by 5 σ in a general case when NP can enter SM-like operators and their chirally-flipped partners. LFU violation is favoured with respect to LFU at the 3-4 σ level. We discuss the impact of LFU-violating New Physics on the observable P 5 ′ from B → K∗μ+μ− and we compare our estimate for long-distance charm contributions with an empirical model recently proposed by a group of LHCb experimentalists. Finally, we discuss NP models able to describe this consistent pattern of deviations.

Survey of Cellular Mobile Radio Localization Methods: From 1G to 5G

Abstract: Cellular systems evolved from a dedicated mobile communication system to an almost omnipresent system with unlimited coverage anywhere and anytime for any device. The growing ubiquity of the network stirred expectations to determine the location of the mobile devices themselves. Since the beginning of standardization, each cellular mobile radio generation has been designed for communication services, and satellite navigation systems, such as Global Positioning System (GPS), have provided precise localization as an add-on service to the mobile terminal. Self-contained localization services relying on the mobile network elements have offered only rough position estimates. Moreover, satellite-based technologies suffer a severe degradation of their localization performance in indoors and urban areas. Therefore, only in subsequent cellular standard releases, more accurate cellular-based location methods have been considered to accommodate more challenging localization services. This survey provides an overview of the evolution of the various localization methods that were standardized from the first to the fourth generation of cellular mobile radio, and looks over what can be expected with the new radio and network aspects for the upcoming generation of fifth generation.

GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia

Abstract: Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health-related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.

Cancer Genome Interpreter annotates the biological and clinical relevance of tumor alterations

Abstract: While tumor genome sequencing has become widely available in clinical and research settings, the interpretation of tumor somatic variants remains an important bottleneck. Here we present the Cancer Genome Interpreter, a versatile platform that automates the interpretation of newly sequenced cancer genomes, annotating the potential of alterations detected in tumors to act as drivers and their possible effect on treatment response. The results are organized in different levels of evidence according to current knowledge, which we envision can support a broad range of oncology use cases. The resource is publicly available at http://www.cancergenomeinterpreter.org .

Search for dark matter and other new phenomena in events with an energetic jet and large missing transverse momentum using the ATLAS detector

Abstract: Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses proton-proton collision data corresponding to an integrated luminosity of 36.1 fb−1 at a centre-of-mass energy of 13 TeV collected in 2015 and 2016 with the ATLAS detector at the Large Hadron Collider. Events are required to have at least one jet with a transverse momentum above 250 GeV and no leptons (e or μ). Several signal regions are considered with increasing requirements on the missing transverse momentum above 250 GeV. Good agreement is observed between the number of events in data and Standard Model predictions. The results are translated into exclusion limits in models with pair-produced weakly interacting dark-matter candidates, large extra spatial dimensions, and supersymmetric particles in several compressed scenarios.

Production and integration of the ATLAS Insertable B-Layer

Abstract: During the shutdown of the CERN Large Hadron Collider in 2013-2014, an additional pixel layer was installed between the existing Pixel detector of the ATLAS experiment and a new, smaller radius beam pipe. The motivation for this new pixel layer, the Insertable B-Layer (IBL), was to maintain or improve the robustness and performance of the ATLAS tracking system, given the higher instantaneous and integrated luminosities realised following the shutdown. Because of the extreme radiation and collision rate environment, several new radiation-tolerant sensor and electronic technologies were utilised for this layer. This paper reports on the IBL construction and integration prior to its operation in the ATLAS detector.

Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study.

Abstract: Summary Background Adding pertuzumab to trastuzumab and chemotherapy improves survival in HER2-positive early breast cancer and metastatic breast cancer. We assessed the efficacy and safety of pertuzumab versus placebo in combination with trastuzumab and chemotherapy in first-line HER2-positive metastatic gastric or gastro-oesophageal junction cancer. Methods JACOB was a double-blind, placebo-controlled, randomised, multicentre, phase 3 trial in patients aged 18 years or older with HER2-positive metastatic gastric or gastro-oesophageal junction cancer. Eligible patients had measurable or evaluable non-measurable disease at baseline, Eastern Cooperative Oncology Group performance status of 0 or 1, and baseline left ventricular ejection fraction of 55% or more. Patients at 197 oncology clinics (in 30 countries) were randomly assigned (1:1) to receive either pertuzumab (840 mg intravenously) or placebo every 3 weeks, with trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks intravenously), plus chemotherapy (cisplatin 80 mg/m 2 every 3 weeks intravenously, oral capecitabine 1000 mg/m 2 twice a day [2000 mg/m 2 every 24 h] for 28 doses every 3 weeks, or 5-fluorouracil 800 mg/m 2 every 24 h intravenously [120 h continuous infusion] every 3 weeks). Randomisation was by a central permuted block randomisation scheme (block size of 4) with an interactive voice or web response system, stratified by geographical region, previous gastrectomy, and HER2 positivity. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with Clinicaltrials.gov, number NCT01774786 (ongoing, but closed to enrolment). Findings Between June 10, 2013, and Jan 12, 2016, of 3287 patients assessed, 780 eligible patients were randomly assigned to receive either pertuzumab plus trastuzumab and chemotherapy (pertuzumab group, n=388) or placebo plus trastuzumab and chemotherapy (control group, n=392). Median duration of follow-up was 24·4 months (95% CI 22·3–26·1) in the pertuzumab group and 25·0 months (22·3–28·9) in the control group. After 242 deaths in the pertuzumab group and 262 deaths in the control group (the study was not stopped at this point), overall survival was not significantly different between treatment groups (median overall survival 17·5 months [95% CI 16·2–19·3] in the pertuzumab group and 14·2 months [12·9–15·5] in the control group; hazard ratio 0·84 [95% CI 0·71–1·00]; p=0·057). Serious adverse events occurred in 175 (45%) of 385 patients in the pertuzumab group and 152 (39%) of 388 patients in the control group. Diarrhoea was the most common serious adverse event in both groups (17 [4%] patients in the pertuzumab group vs 20 [5%] patients in the control group). The most common grade 3–5 adverse events were neutropenia (116 [30%] patients in the pertuzumab group vs 108 [28%] patients in the control group), anaemia (56 [15%] vs 65 [17%]), and diarrhoea (51 [13%] vs 25 [6%]). Treatment-related deaths occurred in seven (2%) patients in the control group; no treatment-related deaths occurred in the pertuzumab group. Interpretation Adding pertuzumab to trastuzumab and chemotherapy did not significantly improve overall survival in patients with HER2-positive metastatic gastric or gastro-oesophageal junction cancer compared with placebo. Further studies are needed to identify improved first-line treatment options in these types of cancer and to identify patients with HER2-driven tumours who might benefit from dual HER2-targeted therapy. Funding F. Hoffmann-La Roche Ltd.

Second consensus on the assessment of sublingual microcirculation in critically ill patients: results from a task force of the European Society of Intensive Care Medicine

Abstract: Hand-held vital microscopes (HVMs) were introduced to observe sublingual microcirculatory alterations at the bedside in different shock states in critically ill patients This consensus aims to provide clinicians with guidelines for practical use and interpretation of the sublingual microcirculation Furthermore, it aims to promote the integration of routine application of HVM microcirculatory monitoring in conventional hemodynamic monitoring of systemic hemodynamic variables In accordance with the Delphi method we organized three international expert meetings to discuss the various aspects of the technology, physiology, measurements, and clinical utility of HVM sublingual microcirculatory monitoring to formulate this consensus document A task force from the Cardiovascular Dynamics Section of the European Society of Intensive Care Medicine (with endorsement of its Executive Committee) created this consensus as an update of a previous consensus in 2007 We classified consensus statements as definitions, requirements, and/or recommendations, with a minimum requirement of 80% agreement of all participants In this consensus the nature of microcirculatory alterations is described The nature of variables, which can be extracted from analysis of microcirculatory images, is presented and the needed dataset of variables to identify microcirculatory alterations is defined Practical aspects of sublingual HVM measurements and the nature of artifacts are described Eleven statements were formulated that pertained to image acquisitions and quality statements Fourteen statements addressed the analysis of the images, and 13 statements are related to future developments This consensus describes 25 statements regarding the acquisition and interpretation of microcirculatory images needed to guide the assessment of the microcirculation in critically ill patients