EPINETLAB:a software for seizure-onset zone identification from intracranial EEG signal in epilepsy

The pre-operative workup of patients with drug-resistant epilepsy requires in some candidates the identification from intracranial EEG (iEEG) of the seizure-onset zone (SOZ), defined as the area responsible of the generation of the seizure and therefore candidate for resection. High-frequency oscillations (HFOs) contained in the iEEG signal have been proposed as biomarker of the SOZ. Their visual identification is a very onerous process and an automated detection tool could be an extremely valuable aid for clinicians, reducing operator-dependent bias and computational time. In this manuscript we present the EPINETLAB software, developed as a collection of routines integrated in the EEGLAB framework that aim to provide clinicians with a structured analysis pipeline for HFOs detection and SOZ identification. The tool implements an analysis strategy developed by our group and underwent a preliminary clinical validation that identifies the HFOs area by extracting the statistical properties of HFOs signal and that provides useful information for a topographic characterization of the relationship between clinically defined SOZ and HFO area. Additional functionalities such as inspection of spectral properties of ictal iEEG data and import and analysis of source-space MEG data were also included. EPINETLAB was developed with user-friendliness in mind to support clinicians in the identification and quantitative assessment of HFOs in iEEG and source space MEG data and aid the evaluation of the SOZ for pre-surgical assessment

No detection of CD4-independent human immunodeficiency virus 1 envelope glycoproteins in brain tissue of patients with or without neurological complications

Macrophage (mac)-tropic human immnunodeficiency virus type 1 (HIV-1) and simian immnunodeficiency virus (SIV) in brain are associated with neurological disease. Mac-tropic HIV-1 evolves enhanced CD4 interactions that enable macrophage infection via CD4, which is in low abundance. In contrast, mac-tropic SIV is associated with CD4-independent infection via direct CCR5 binding. Recently, mac-tropic simian-human immunodeficiency virus (SHIV) from macaque brain was also reported to infect cells via CCR5 without CD4. Since SHIV envelope proteins (Envs) are derived from HIV-1, we tested more than 100 HIV-1 clade B Envs for infection of CD4-negative, CCR5(+) Cf2Th/CCR5 cells. However, no infection was detected. Our data suggest that there are differences in the evolution of mac-tropism in SIV and SHIV compared to HIV-1 clade B due to enhanced interactions with CCR5 and CD4, respectively

Is there a relationship between joint hypermobility and gastrointestinal disorders in children?

Background. The main aim of the study was to assess the association between joint hypermobility (JH) and gastrointestinal (GI) disorders in children. Methods. All children aged 4-17 years attending the clinics of the participating Pediatric Gastroenterology Centres for functional GI disorders (FGIDs) and inflammatory bowel disease (IBD) were screened for joint laxity. JH diagnosis was inferred using the Beighton Score. JHS diagnosis was inferred based on the Brighton Criteria. Rome III Diagnostic Criteria were used to diagnose possible FGIDs. Ulcerative colitis and Crohn’s disease diagnoses were made according to the Porto Criteria. Age and sex- matched healthy children were enrolled as controls. Results. One-hundred-seventy children with GI disorders (70 with FGIDs, 50 with Crohn’s disease, and 50 with ulcerative colitis) and 100 healthy controls were enrolled in the study. JH was reported in 7/70 (10%) children with FGIDs (p=0.26 compared to controls), 4/50 (8%) children with Crohn’s disease (p=0.21 compared to controls) and 15/50 (30%) children with ulcerative colitis (p=0.09 compared to controls; p=0.01 compared to FGIDs; p=0.01 compared to Crohn’s). Conclusions. JH is more prevalent in patients suffering from ulcerative colitis compared to the healthy general population, yet the difference did not reach statistical significance. Likely, a proportion of children with ulcerative colitis and JH may show connective tissue abnormalities. However, whether JH can be considered a possible feature of pediatric GI disorders deserves further investigation

Societal issues concerning the application of artificial intelligence in medicine

Medicine is becoming an increasingly data-centred discipline and, beyond classical statistical approaches, artificial intelligence (AI) and, in particular, machine learning (ML) are attracting much interest for the analysis of medical data. It has been argued that AI is experiencing a fast process of commodification. This characterization correctly reflects the current process of industrialization of AI and its reach into society. Therefore, societal issues related to the use of AI and ML should not be ignored any longer and certainly not in the medical domain. These societal issues may take many forms, but they all entail the design of models from a human-centred perspective, incorporating human-relevant requirements and constraints. In this brief paper, we discuss a number of specific issues affecting the use of AI and ML in medicine, such as fairness, privacy and anonymity, explainability and interpretability, but also some broader societal issues, such as ethics and legislation. We reckon that all of these are relevant aspects to consider in order to achieve the objective of fostering acceptance of AI- and ML-based technologies, as well as to comply with an evolving legislation concerning the impact of digital technologies on ethically and privacy sensitive matters. Our specific goal here is to reflect on how all these topics affect medical applications of AI and ML. This paper includes some of the contents of the “2nd Meeting of Science and Dialysis: Artificial Intelligence,” organized in the Bellvitge University Hospital, Barcelona, Spain.Peer ReviewedPostprint (author's final draft

HIV-1 R5 Macrophage-Tropic Envelope Glycoprotein Trimers Bind CD4 with High Affinity, while the CD4 Binding Site on Non-macrophage-tropic, T-Tropic R5 Envelopes Is Occluded

HIV-1 R5 variants exploit CCR5 as a coreceptor to infect both T cells and macrophages. R5 viruses that are transmitted or derived from immune tissue and peripheral blood are mainly inefficient at mediating infection of macrophages. In contrast, highly macrophage-tropic (mac-tropic) R5 viruses predominate in brain tissue and can be detected in cerebrospinal fluid but are infrequent in immune tissue or blood even in late disease. These mac-tropic R5 variants carry envelope glycoproteins (Envs) adapted to exploit low levels of CD4 on macrophages to induce infection. However, it is unclear whether this adaptation is conferred by an increased affinity of the Env trimer for CD4 or is mediated by postbinding structural rearrangements in the trimer that enhance the exposure of the coreceptor binding site and facilitate events leading to fusion and virus entry. In this study, we investigated CD4 binding to mac-tropic and non-mac-tropic Env trimers and showed that CD4-IgG binds efficiently to mac-tropic R5 Env trimers, while binding to non-mac-tropic trimers was undetectable. Our data indicated that the CD4 binding site (CD4bs) is highly occluded on Env trimers of non-mac-tropic R5 viruses. Such viruses may therefore infect T cells via viral synapses where Env and CD4 become highly concentrated. This environment will enable high-avidity interactions that overcome extremely low Env-CD4 affinities. IMPORTANCE HIV R5 variants bind to CD4 and CCR5 receptors on T cells and macrophages to initiate infection. Transmitted HIV variants infect T cells but not macrophages, and these viral strains persist in immune tissue even in late disease. Here we show that the binding site for CD4 present on HIV\u27s envelope protein is occluded on viruses replicating in immune tissue. This occlusion likely prevents antibody binding to this site and neutralization of the virus, but it makes it difficult for virus-CD4 interactions to occur. Such viruses probably pass from T cell to T cell via cell contacts where CD4 is highly concentrated and allows infection via inefficient envelope-CD4 binding. Our data are highly relevant for vaccines that aim to induce antibodies targeting the CD4 binding site on the envelope protein

Efficiency of bridging-sheet recruitment explains HIV-1 R5 envelope glycoprotein sensitivity to soluble CD4 and macrophage tropism

HIV-1 R5 viruses vary extensively in their capacity to infect macrophages. R5 viruses that confer efficient infection of macrophages are able to exploit low levels of CD4 for infection and predominate in brain tissue, where macrophages are a major target for infection. HIV-1 R5 founder viruses that are transmitted were reported to be non-macrophage-tropic. Here, we investigated the sensitivities of macrophage-tropic and non-macrophage-tropic R5 envelopes to neutralizing antibodies. We observed striking differences in the sensitivities of Env(+) pseudovirions to soluble CD4 (sCD4) and to neutralizing monoclonal antibodies (MAbs) that target the CD4 binding site. Macrophage-tropic R5 Envs were sensitive to sCD4, while non-macrophage-tropic Envs were significantly more resistant. In contrast, all Envs were sensitive to VRC01 regardless of tropism, while MAb b12 conferred an intermediate neutralization pattern where all the macrophage-tropic and about half of the non-macrophage-tropic Envs were sensitive. CD4, b12, and VRC01 share binding specificities on the outer domain of gp120. However, these antibodies differ in their ability to induce conformational changes on the trimeric envelope and in specificity for residues on the V1V2 loop stem and beta20-21 junction that are targets for CD4 in recruiting the bridging sheet. These distinct specificities of CD4, b12, and VRC01 likely explain the observed differences in Env sensitivity to inhibition by these reagents and provide an insight into the envelope mechanisms that control macrophage tropism. We present a model where the efficiency of bridging-sheet recruitment by CD4 is a major determinant of HIV-1 R5 envelope sensitivity to soluble CD4 and macrophage tropism

Teaching Robust Argumentation Informed by the Nature of Science to Support Social Justice. Experiences from Two Projects in Lower Secondary Schools in Norway

Under embargo until: 2022-09-09This chapter suggests a set of design principles for science curricula that will enable students to produce evidence-based arguments expressing views related to their own interests. It is based on the assumption that the ability to construct evidence-based arguments strengthens students’ ability to promote their own views in the interest of social justice. This is of special importance for students not enculturated into such argumentation through their upbringing. To promote one’s own views in a debate means to critique others’ arguments, and especially to ensure one’s own arguments are resistent to criticism. Insight into the nature of science includes insights in how to construct sound arguments based on facts and research results. The discussion of design principles is based on an analysis of two science projects in two lower secondary schools in Norway (Grade 8). In the first project, students produced scientific claims based on evidence from their own practical experiments. In the second project, the students developed and applied a method for estimating energy use and carbon dioxide (CO2) emissions. The students used their findings to construct arguments related to local transport plans. The analysis focuses on challenges and successes in scaffolding students at different competence levels to successfully produce evidence-based arguments.acceptedVersio

Cognitive processing in non-communicative patients:what can event-related potentials tell us?

Event-related potentials (ERP) have been proposed to improve the differential diagnosis of non-responsive patients. We investigated the potential of the P300 as a reliable marker of conscious processing in patients with locked-in syndrome (LIS). Eleven chronic LIS patients and 10 healthy subjects (HS) listened to a complex-tone auditory oddball paradigm, first in a passive condition (listen to the sounds) and then in an active condition (counting the deviant tones). Seven out of nine HS displayed a P300 waveform in the passive condition and all in the active condition. HS showed statistically significant changes in peak and area amplitude between conditions. Three out of seven LIS patients showed the P3 waveform in the passive condition and five of seven in the active condition. No changes in peak amplitude and only a significant difference at one electrode in area amplitude were observed in this group between conditions. We conclude that, in spite of keeping full consciousness and intact or nearly intact cortical functions, compared to HS, LIS patients present less reliable results when testing with ERP, specifically in the passive condition. We thus strongly recommend applying ERP paradigms in an active condition when evaluating consciousness in non-responsive patients

Cyclic vomiting syndrome in children: a nationwide survey of current practice on behalf of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) and Italian Society of Pediatric Neurology (SINP)

Background: Cyclic Vomiting Syndrome (CVS) is a rare functional gastrointestinal disorder, which has a considerable burden on quality of life of both children and their family. Aim of the study was to evaluate the diagnostic modalities and therapeutic approach to CVS among Italian tertiary care centers and the differences according to subspecialties, as well as to explore whether potential predictive factors associated with either a poor outcome or a response to a specific treatment. Methods: Cross-sectional multicenter web-based survey involving members of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) and Italian Society of Pediatric Neurology (SINP). Results: A total of 67 responses were received and analyzed. Most of the respondent units cared for less than 20 patients. More than half of the patients were referred after 3 to 5 episodes, and a quarter after 5 attacks. We report different diagnostic approaches among Italian clinicians, which was particularly evident when comparing gastroenterologists and neurologists. Moreover, our survey demonstrated a predilection of certain drugs during emetic phase according to specific clinic, which reflects the cultural background of physicians. Conclusion: In conclusion, our survey highlights poor consensus amongst clinicians in our country in the diagnosis and the management of children with CVS, raising the need for a national consensus guideline in order to standardize the practice

An integrated map of structural variation in 2,504 human genomes

Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multiple breakpoints likely to have formed through individual mutational events. Our catalogue will enhance future studies into structural variant demography, functional impact and disease association. © 2015 Macmillan Publishers Limited. All rights reserved