Monitoring of anticoagulation in thrombotic antiphospholipid syndrome

Anticoagulation is central to the management of thrombotic antiphospholipid syndrome (APS). The standard anticoagulant treatment for thrombotic APS is life-long warfarin or an alternative vitamin K antagonist. The role of direct oral anticoagulants for thrombotic APS is not established due to the lack of definitive evidence and has recently been addressed in international guidance. Other anticoagulant options include low molecular weight heparin, unfractionated heparin, and fondaparinux. In APS patients, lupus anticoagulant can affect phospholipid-dependent coagulation monitoring tests, so that they may not reflect true anticoagulation intensity. Accurate assessment of anticoagulation intensity is essential, to optimize anticoagulant dosing and facilitate thrombus resolution; minimize the risk of recurrent thrombosis or bleeding; inform assessment of whether recurrent thrombosis is related to breakthrough thrombosis while on therapeutic anticoagulation, subtherapeutic anticoagulation, non-adherence, or spurious results; and guide the management of bleeding. Knowledge of anticoagulant intensity also informs assessment and comparison of anticoagulation regimens in clinical studies. Considerations regarding anticoagulation dosing and/or monitoring of thrombotic APS patients underpin appropriate management in special situations, notably APS-related severe renal impairment, which can occur in APS or APS/systemic lupus erythematosus-related nephropathy or catastrophic APS; and APS-related thrombocytopenia. Anticoagulant dosing and monitoring in thrombotic APS patients also require consideration in anticoagulant-refractory APS and during pregnancy. In this review, we summarize the tests generally used in monitoring anticoagulant therapy, use of the main anticoagulants considered for thrombotic APS, lupus anticoagulant effects on anticoagulation monitoring tests, and strategies for appropriate anticoagulant monitoring in thrombotic APS

The Loneliness of Migraine Scale: A Development and Validation Study

Patients with migraine often isolate themselves during their attacks. This disease-related loneliness seems to reverberate interictal, as some patients report failing relationships, losing jobs, or suffering from reduced social contacts. We developed a 10-item self-report questionnaire, the loneliness of migraine scale (LMS), and conducted an online survey. The questionnaire comprised diagnostic questions for migraine, the loneliness of migraine scale, the Generalized Anxiety Disorder Scale (GAD-7), the Patient Health Questionnaire (PHQ-8), and the Headache Attributed Lost Time Index (HALT-90). We computed item statistics, the psychometric properties of the LMS and assessed correlations between loneliness, migraine days, anxiety, and depression. We included 223 participants with (probable) migraine, reporting 8 ± 6 headache days with a disease duration of 11 ± 11 years. The mean scores of the HALT were 88 ± 52, of the GAD-7 10 ± 5, for PHQ-8 11 ± 6, and of the LMS 28.79 ± 9.72. Cronbach’s alpha for all ten items was 0.929. The loneliness scale correlated with the GAD-7 (r = 0.713, p < 0.001), with the PHQ-8 scale (r = 0.777, p < 0.001) and with migraine days (r = 0.338, p < 0.001). The LMS is a reliable and valid questionnaire measuring the loneliness of migraine patients. Feelings of loneliness were common and correlated highly with migraine days, anxiety, and depression

A one-point increase in the Damage Index for Antiphospholipid Syndrome (DIAPS) predicts mortality in thrombotic antiphospholipid syndrome

OBJECTIVES: To determine whether early damage and its kinetics measured by the Damage Index for Antiphospholipid Syndrome (DIAPS) predicts mortality. METHODS: We carried out a single-centre retrospective analysis of thrombotic APS patients (2006 Sydney criteria), using the DIAPS for damage assessment. Early damage was considered to be at six months after disease onset; early damage increase (delta-DIAPS) was deemed to be at least a one-point rise in DIAPS within the first five years of illness. Groups were compared using appropriate statistical tests. Survival was analysed by the Kaplan-Meier method. Cox regression analysis was performed to investigate predictors of mortality. RESULTS: A total of 197 patients (71.1% female; 65.9% primary APS; 72.4% Caucasian) were followed for up to 43 years (median 10). Damage developed in 143 (73.6%) patients. Twenty-three patients (12%) died. Secondary APS (HR 3.07, 95%CI 1.32-7.12, p=0.009), male sex (HR 3.14, 95%CI 1.35-7.33, p=0.008) and age at APS onset ≥40 years (HR 5.34, 95%CI 1.96-14.53, p=0.001) were risk factors for death. Early damage (n=69, 35.0%) was not associated with death (p=0.231). Having a first arterial event was associated with early damage (p<0.001), but not with delta-DIAPS (p=0.539) nor with the risk of death (p=0.151). Delta-DIAPS (n=53/181, 29.3%) predicted mortality (HR 5.40, 95%CI 2.33-12.52, p<0.001), even after adjusting individually for APS category (secondary), sex (male), early damage and age at APS onset (≥40 years) (all p<0.005). CONCLUSIONS: Evolving damage in the first five years of illness, but not early damage, predicted mortality regardless of the nature of the first thrombotic event, sex, APS category and age

Ψυχολογία αθλητών αντισφαίρισης στις αναπτυξιακές ηλικίες

Ο σκοπός αυτής της εργασίας ήταν να ερευνηθούν οι ιδιότητες του άγχους και της ανησυχίας καθώς και η σχέση τους με την απόδοση σε παίδες κι έφηβους αθλητές της αντισφαίρισης. Η ικανότητα αντιμετώπισης των παραγόντων της πίεσης και του άγχους αποτελεί ένα αναπόσπαστο μέρος του αθλητισμού. Για τις ανάγκες του σκοπού της εργασίας πραγματοποιήθηκε βιβλιογραφική ανασκόπηση καθώς και έρευνα στην οποία χρησιμοποιήθηκε το ερωτηματολόγιο των Α. Λιάκου και C.D. Spielberger State Trait Anxiety Inventory STAI το οποίο αποτελεί Ερωτηματολόγιο αξιολόγηση άγχους. Οι συμμετέχοντες σ’ αυτή την έρευνα ήταν 20 άτομα συνολικά, 10-13 ετών τα οποία ήταν αθλητές/τριες τένις. Οι αθλητές/τριες προέρχονται και αθλούνται στο σύλλογο αντισφαίρισης Εκπαιδευτηρίων Δούκα. Μοιράστηκαν και συλλέχθηκαν 20 ερωτηματολόγια. Τα ερωτηματολόγια ήταν σωστά συμπληρωμένα και υπήρχε βοήθεια καθ’ όλη την διάρκεια συμπλήρωσής τους από τις συντάκτριες. Η περίοδος που μοιράστηκαν τα ερωτηματολόγια ήταν τον Μάιο – Ιούνιο 2016. Υπήρξε η συγκατάθεση των γονιών - κηδεμόνων των παιδιών για την συμπλήρωση των ερωτηματολογίων οι οποίοι παρευρίσκονταν καθ’ όλη την διάρκεια της συμπλήρωσης του ερωτηματολογίου. Οι ίδιοι έκριναν ότι τα παιδιά δεν καταλαβαίνουν την έννοια των ερωτήσεων 18, 20 (οι οποίες και απευθύνονται σε μεγαλύτερης ηλικίας άτομα) και οι οποίες δεν απαντήθηκαν από τα παιδιά. Η ανάπτυξη του CSAI-2 επιτρέπει στους ερευνητές την αξιόπιστη μέτρηση του γνωστικού άγχους, του σωματικού άγχους, του βαθμού αυτοπεποίθησης και της έλλειψης συγκέντρωσης του ατόμου. Επιπροσθέτως, η ανάπτυξη των πολλαπλών σχεδιασμών έρευνας παρέχει μία μέθοδο για την εξέταση των παρεμβάσεων της μείωσης του άγχους. Θα πρέπει να δοθεί ιδιαίτερη προσοχή στις ανάγκες των αθλητών, στο πλαίσιο της αθλητικής ψυχολογίας ώστε να υπάρξει το καλύτερο δυνατό αποτέλεσμα.Ν

Fluctuation of Anti-Domain 1 and Anti-Β2 Glycoprotein I Antibody Titers Over Time in Patients with Persistently Positive Antiphospholipid Antibodies

OBJECTIVE: This work aims at evaluating longitudinally titers of antibodies against β2-glycoprotein I (β2GPI) and domain 1 (anti-D1), identifying predictors of the variation of anti-D1 and anti-β2GPI antibody titers and clarifying whether antibody titer fluctuations predict thrombosis in a large international cohort of patients persistently positive for antiphospholipid antibodies (aPL), the "APS ACTION Registry". METHODS: Patients with available blood samples from at least 4 time points were included. Anti-β2GPI and anti-D1 IgG were tested by chemiluminescence (BioFlash, INOVA Diagnostics). RESULTS: In a cohort of 230 patients, anti-D1 and anti-β2GPI titers decreased significantly over time (p<0.0001 and p=0.010, respectively). After adjustment for age, gender, and number of positive aPL tests, the fluctuation of anti-D1 and anti-β2GPI titers was associated with treatment with hydroxychloroquine (HCQ) at each time-point. Treatment with HCQ, but not immunosuppressors, was associated with 1.3-fold and 1.4-fold decrease in anti-D1 and anti-β2GPI titers, respectively. Incident vascular events were associated with 1.9-fold and 2.1-fold increase of anti-D1 and anti-β2GPI titers, respectively. Anti-D1 and anti-β2GPI titers at the time of thrombosis were lower compared to the other time-points: 1.6-fold decrease in anti-D1 titers and 2-fold decrease in anti-β2GPI titers conferred an OR for incident thrombosis of 6.0 (95%CI 0.62-59.3) and 9.4 (95%CI 1.1-80.2), respectively. CONCLUSIONS: Treatment with HCQ and incident vascular events significant predicted anti-D1 and anti-β2GPI titer fluctuation over time. Both anti-D1 and anti-β2GPI titers drop around the time of thrombosis, with potential clinical relevance. This article is protected by copyright. All rights reserved

Optically reconfigurable molecules of topological bound states in the continuum

Symmetry protected optical bound states in the continuum (BICs) are charming wave-mechanical objects that provide new and exciting ways to enhance light-matter interactions in compact photonic devices. These ultrahigh quality factor states have quickly transcended from passive structures, and lasing devices in the weak-coupling regime, towards nonequilibrium Bose-Einstein condensates of BIC polaritons in the strong-coupling regime. Here, we show that the large interaction strength of exciton-polaritons in subwavelength quantum-well waveguide gratings in conjunction with their topologically protected BIC nature opens unexplored opportunities in low-threshold optically reprogrammable quantum fluids. The BIC causes polaritons to -- almost counterintuitively -- condense in the extremum of a negative mass dispersion which leads to strong interaction-induced trapping at their respective pump spot and gain region. We exploit this optical trapping mechanism to demonstrate macroscopic mode-hybridization, the hallmark of coherent quantum systems, enabling construction of never-seen-before artificial BIC molecules with unusual topological charge mutliplicity. We underpin the optical write-in aspect of our technique by constructing, on the same sample, artificial mono-atomic and dimerized BIC chains of polariton fluids displaying non-Hermitian quasicrystalline band formation and gap opening. Our findings open new perspectives on large-scale reprogrammable driven dissipative many-body systems in the strong-coupling regime

Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination

Progressive limb spasticity and cerebellar ataxia are frequently found together in clinical practice and form a heterogeneous group of degenerative disorders that are classified either as pure spastic ataxia or as complex spastic ataxia with additional neurological signs. Inheritance is either autosomal dominant or autosomal recessive. Hypomyelinating features on MRI are sometimes seen with spastic ataxia, but this is usually mild in adults and severe and life limiting in children. We report seven individuals with an early-onset spastic-ataxia phenotype. The individuals come from three families of different ethnic backgrounds. Affected members of two families had childhood onset disease with very slow progression. They are still alive in their 30s and 40s and show predominant ataxia and cerebellar atrophy features on imaging. Affected members of the third family had a similar but earlier-onset presentation associated with brain hypomyelination. Using a combination of homozygozity mapping and exome sequencing, we mapped this phenotype to deleterious nonsense or homeobox domain missense mutations in NKX6-2. NKX6-2 encodes a transcriptional repressor with early high general and late focused CNS expression. Deficiency of its mouse ortholog results in widespread hypomyelination in the brain and optic nerve, as well as in poor motor coordination in a pattern consistent with the observed human phenotype. In-silico analysis of human brain expression and network data provides evidence that NKX6-2 is involved in oligodendrocyte maturation and might act within the same pathways of genes already associated with central hypomyelination. Our results support a non-redundant developmental role of NKX6-2 in humans and imply that NKX6-2 mutations should be considered in the differential diagnosis of spastic ataxia and hypomyelination.Fil: Chelban, Viorica. University College London; Estados Unidos. Institute of Emergency Medicine; MoldaviaFil: Patel, Nisha. King Faisal Specialist Hospital and Research Center; Arabia SauditaFil: Vandrovcova, Jana. University College London; Estados UnidosFil: Zanetti, Maria Natalia. University College London; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Lynch, David S.. University College London; Estados UnidosFil: Ryten, Mina. University College London; Estados Unidos. King’s College London; Reino UnidoFil: Botía, Juan A.. University College London; Estados Unidos. Universidad de Murcia; EspañaFil: Bello, Oscar Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina. University College London; Estados UnidosFil: Tribollet, Eloise. University College London; Estados UnidosFil: Efthymiou, Stephanie. University College London; Estados UnidosFil: Davagnanam, Indran. University College London; Estados UnidosFil: Bashiri, Fahad A.. King Saud University; Arabia SauditaFil: Wood, Nicholas W.. University College London; Estados Unidos. The National Hospital for Neurology and Neurosurgery; Reino UnidoFil: Rothman, James E.. University of Yale. School of Medicine; Estados Unidos. University College London; Estados UnidosFil: Alkuraya, Fowzan S.. King Faisal Specialist Hospital and Research Center; Arabia Saudita. Alfaisal University; Arabia Saudita. King Abdulaziz City for Science and Technology; Arabia SauditaFil: Houlden, Henry. The National Hospital for Neurology and Neurosurgery; Reino Unido. University College London; Estados Unido

The adjusted global antiphospholipid syndrome score (aGAPSS) and the risk of recurrent thrombosis: Results from the APS ACTION cohort

Objectives: To assess whether patients with antiphospholipid syndrome (APS) and history of recurrent thrombosis have higher levels of adjusted Global AntiphosPholipid Syndrome Score (aGAPSS) when compared to patients without recurrent thrombosis. Methods: In this cross-sectional study of antiphospholipid antibody (aPL)-positive patients, we identified APS patients with a history of documented thrombosis from the AntiPhospholipid Syndrome Alliance For Clinical Trials and InternatiOnal Networking (APS ACTION) Clinical Database and Repository (“Registry”). Data on aPL-related medical history and cardiovascular risk factors were retrospectively collected. The aGAPSS was calculated at Registry entry by adding the points corresponding to the risk factors: three for hyperlipidemia, one for arterial hypertension, five for positive anticardiolipin antibodies, four for positive anti-β2 glycoprotein-I antibodies and four for positive lupus anticoagulant test. Results: The analysis included 379 APS patients who presented with arterial and/or venous thrombosis. Overall, significantly higher aGAPSS were seen in patients with recurrent thrombosis (arterial or venous) compared to those without recurrence (7.8 ± 3.3 vs. 6 ± 3.9, p<0.05). When analyzed based on the site of the recurrence, patients with recurrent arterial, but not venous, thrombosis had higher aGAPSS (8.1 ± SD 2.9 vs. 6 ± 3.9; p<0.05). Conclusions: Based on analysis of our international large-scale Registry of aPL-positive patients, the aGAPSS might help risk stratifying patients based on the likelihood of developing recurrent thrombosis in APS

Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment

VAMP2 encodes the vesicular SNARE protein VAMP2 (also called synaptobrevin-2). Together with its partners syntaxin-1A and synaptosomal-associated protein 25 (SNAP25), VAMP2 mediates fusion of synaptic vesicles to release neurotransmitters. VAMP2 is essential for vesicular exocytosis and activity-dependent neurotransmitter release. Here, we report five heterozygous de novo mutations in VAMP2 in unrelated individuals presenting with a neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features. In total, we identified two single-amino-acid deletions and three non-synonymous variants affecting conserved residues within the C terminus of the VAMP2 SNARE motif. Affected individuals carrying de novo non-synonymous variants involving the C-terminal region presented a more severe phenotype with additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities. Reconstituted fusion involving a lipid-mixing assay indicated impairment in vesicle fusion as one of the possible associated disease mechanisms. The genetic synaptopathy caused by VAMP2 de novo mutations highlights the key roles of this gene in human brain development and function