Diagnosis and management of the antiphospholipid syndrome

The antiphospholipid syndrome is a systemic autoimmune disease defined by thrombotic or obstetrical events that occur in patients with persistent antiphospholipid antibodies. Thrombotic antiphospholipid syndrome is characterized by venous, arterial, or microvascular thrombosis. Patients with catastrophic antiphospholipid syndrome present with thrombosis involving multiple organs. Obstetrical antiphospholipid syndrome is characterized by fetal loss after the 10th week of gestation, recurrent early miscarriages, intrauterine growth restriction, or severe preeclampsia.1 The major nonthrombotic manifestations of antiphospholipid-antibody positivity include valvular heart disease, livedo, antiphospholipidantibody-related nephropathy, thrombocytopenia, hemolytic anemia, and cognitive dysfunction. The antiphospholipid syndrome is often associated with other systemic autoimmune diseases such as systemic lupus erythematosus (SLE); however, it commonly occurs without other autoimmune manifestations (primary antiphospholipid syndrome)

Downlink scheduling and resource allocation for 5G MIMO-multicarrier: OFDM vs FBMC/OQAM

OAPA The definition of the next generation of wireless communications, so-called 5G networks, is currently underway. Among many technical decisions, one that is particularly fundamental is the choice of the physical layer modulation format and waveform, an issue for which several alternatives have been proposed. Two of the most promising candidates are: (i) orthogonal frequency division multiple (OFDM), a conservative proposal that builds upon the huge legacy of 4G networks, and (ii) filterbank multicarrier/offset quadrature amplitude modulation (FBMC/OQAM), a progressive approach that in frequency selective channels sacrifices subcarrier orthogonality in lieu of an increased spectral efficiency. The comparative merits of OFDM and FBMC/OQAM have been well investigated over the last few years but mostly, from a purely physical layer point of view and largely neglecting how the physical layer performance translates into user-relevant metrics at the upper-layers. This paper aims at presenting a comprehensive comparison of both modulation formats in terms of practical network indicators such as goodput, delay, fairness and service coverage, and under operational conditions that can be envisaged to be realistic in 5G deployments. To this end, a unifying cross-layer framework is proposed that encompasses the downlink scheduling and resource allocation procedures and that builds upon a model of the queueing process at the data-link control layer and a physical layer abstraction that can be chosen to model either OFDM or FBMC/OQAM. Extensive numerical results conclusively demonstrate that most of the apriori advantages of FBMC/OQAM over OFDM do indeed translate into improved network indicators, that is, the increase in spectral efficiency achieved by FBMC/OQAM makes up for the distortion caused by the loss of orthogonality.Peer ReviewedPostprint (published version

Predicting effects of structural stress in a genome-reduced model bacterial metabolism

Mycoplasma pneumoniae is a human pathogen recently proposed as a genome-reduced model for bacterial systems biology. Here, we study the response of its metabolic network to different forms of structural stress, including removal of individual and pairs of reactions and knockout of genes and clusters of co-expressed genes. Our results reveal a network architecture as robust as that of other model bacteria regarding multiple failures, although less robust against individual reaction inactivation. Interestingly, metabolite motifs associated to reactions can predict the propagation of inactivation cascades and damage amplification effects arising in double knockouts. We also detect a significant correlation between gene essentiality and damages produced by single gene knockouts, and find that genes controlling high-damage reactions tend to be expressed independently of each other, a functional switch mechanism that, simultaneously, acts as a genetic firewall to protect metabolism. Prediction of failure propagation is crucial for metabolic engineering or disease treatment

Detecting the significant flux backbone of Escherichia coli metabolism

The heterogeneity of computationally predicted reaction fluxes in metabolic networks within a single flux state can be exploited to detect their significant flux backbone. Here, we disclose the backbone of Escherichia coli, and compare it with the backbones of other bacteria. We find that, in general, the core of the backbones is mainly composed of reactions in energy metabolism corresponding to ancient pathways. In E. coli, the synthesis of nucleotides and the metabolism of lipids form smaller cores which rely critically on energy metabolism. Moreover, the consideration of different media leads to the identification of pathways sensitive to environmental changes. The metabolic backbone of an organism is thus useful to trace simultaneously both its evolution and adaptation fingerprints

Essential plasticity and redundancy of metabolism unveiled by synthetic lethality analysis

We unravel how functional plasticity and redundancy are essential mechanisms underlying the ability to survive of metabolic networks. We perform an exhaustive computational screening of synthetic lethal reaction pairs in Escherichia coli in a minimal medium and we find that synthetic lethal pairs divide in two different groups depending on whether the synthetic lethal interaction works as a backup or as a parallel use mechanism, the first corresponding to essential plasticity and the second to essential redundancy. In E. coli, the analysis of pathways entanglement through essential redundancy supports the view that synthetic lethality affects preferentially a single function or pathway. In contrast, essential plasticity, the dominant class, tends to be inter-pathway but strongly localized and unveils Cell Envelope Biosynthesis as an essential backup for Membrane Lipid Metabolism. When comparing E. coli and Mycoplasma pneumoniae, we find that the metabolic networks of the two organisms exhibit a large difference in the relative importance of plasticity and redundancy which is consistent with the conjecture that plasticity is a sophisticated mechanism that requires a complex organization. Finally, coessential reaction pairs are explored in different environmental conditions to uncover the interplay between the two mechanisms. We find that synthetic lethal interactions and their classification in plasticity and redundancy are basically insensitive to medium composition, and are highly conserved even when the environment is enriched with nonessential compounds or overconstrained to decrease maximum biomass formation

Translational medicine in hereditary hemorrhagic telangiectasia

Scientific community have gained lots of new insights in the genetic and biochemical background of different conditions, rare diseases included, settling the basis for preclinical models that are helping to identify new biomarkers and therapeutic targets. Translational Medicine (TM) is an interdisciplinary area of biomedicine with an essential role in bench-to-bedside transition enhancement, generating a circular flow of knowledge transference between research environment and clinical setting, always centered in patient needs. Here, we present different tools used in TM and an overview of what is being done related to hereditary hemorrhagic telangiectasia (HHT), as a disease's model. This work is focused on how this combination of basic and clinical research impacts in HHT patient's daily clinical management and also looking into the future. Further randomized clinical trials with HHT patients should assess the findings of this bench-to-bedside transition. The benefits of this basic and clinical research combination, may not only be important for HHT patients but for patients with other vascular diseases sharing angiogenic disturbances

Aflibercept for Gastrointestinal Bleeding in Hereditary Hemorrhagic Telangiectasia: A Case Report.

Herein, we present the first described hereditary hemorrhagic telangiectasia (HHT) pa- tient treated with aflibercept for severe GI involvement after tachyphylaxis to bevacizumab, with promising results. HHT is a rare genetic disease characterized by systemic vascular malformations. Gastrointestinal telangiectasia is one of the major involvements that can produce chronic severe iron-deficiency anemia. Nowadays, support treatment with iron replacement therapy, red blood cell transfusions, and antiangiogenic drugs—mainly bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF)—are the main therapeutic options for this complication. The evidence of alternative drugs in patients with failure to this approach, such as tachyphylaxis to bevacizumab, is scarce. Aflibercept is a VEGF inhibitor with antiangiogenic properties approved for the treatment of different types of cancer and ocular neovascularization diseases

Singulto persistente secundario a COVID-19

Singultus (commonly known as hiccups) are involuntary, spasmodic contractions of the diaphragm and the intercostal muscles. It is mainly secondary to benign conditions. We present the case of an 83-year-old man who, after hospital discharge for COVID-19, presents persistent singultus. It finally resolved after treatment with dexamethasone.El singulto (comúnmente conocido como hipo) es una contracción espasmódica e involuntaria del diafragma y los músculos intercostales. La mayoría de los casos son secundarios a etiología benigna. Presentamos el caso de un hombre de 83 años que, tras el alta hospitalaria por COVID-19, presenta singulto persistente. Finalmente, se resolvió con tratamiento con dexametasona

PICO Questions and DELPHI Methodology for the Management of Venous Thromboembolism Associated with COVID-19

COVID-19; Anticoagulació; Malaltia tromboembòlica venosaCOVID-19; Anticoagulación; Enfermedad tromboembólica venosaCOVID-19; Anticoagulation; Venous thromboembolic diseasePatients with coronavirus disease 2019 (COVID-19) have a higher risk of venous thromboembolic disease (VTE) than patients with other infectious or inflammatory diseases, both as macrothrombosis (pulmonar embolism and deep vein thrombosis) or microthrombosis. However, the use of anticoagulation in this scenario remains controversial. This is a project that used DELPHI methodology to answer PICO questions related to anticoagulation in patients with COVID-19. The objective was to reach a consensus among multidisciplinary VTE experts providing answers to those PICO questions. Seven PICO questions regarding patients with COVID-19 responded with a broad consensus: 1. It is recommended to avoid pharmacological thromboprophylaxis in most COVID-19 patients not requiring hospital admission; 2. In most hospitalized patients for COVID-19 who are receiving oral anticoagulants before admission, it is recommended to replace them by low molecular weight heparin (LMWH) at therapeutic doses; 3. Thromboprophylaxis with LMWH at standard doses is suggested for COVID-19 patients admitted to a conventional hospital ward; 4. Standard-doses thromboprophylaxis with LMWH is recommended for COVID-19 patients requiring admission to Intensive Care Unit; 5. It is recommended not to determine D-Dimer levels routinely in COVID-19 hospitalized patients to select those in whom VTE should be suspected, or as a part of the diagnostic algorithm to rule out or confirm a VTE event; 6. It is recommended to discontinue pharmacological thromboprophylaxis at discharge in most patients hospitalized for COVID-19; 7. It is recommended to withdraw anticoagulant treatment after 3 months in most patients with a VTE event associated with COVID-19. The combination of PICO questions and DELPHI methodology provides a consensus on different recommendations for anticoagulation management in patients with COVID-19.This work was carried out with the institutional support and unconditional financial assistance of Sanofi, which had no role in the design, interpretation, or writing of the manuscript