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In this paper, we develop a new dataset on indirect state rivalry relations based on different matrix calculations for 154 countries, over the period 1970-2015, and demonstrate their importance in explaining civil wars. After controlling for spatial distances between rival countries, we demonstrate that 1) the presence of direct and indirect rivals exerts a positive and significant effect on the risk of civil war; 2) decreasing levels of military capacity of one state relative to its rivals (direct and indirect) also influence the probability of internal conflict. Finally, we confirm the significance of our indicators by using on the one hand the random forest algorithm, a machine learning method using decision trees and on the other hand, the Kaplan-Meier estimate for the duration of the civil wars. [ABSTRACT FROM AUTHOR]

Introduction: With recent approval of the first two gene therapies for haemophilia A and B, educational materials about AAV‐based gene therapy are needed by the haemophilia community for a better understanding of this novel therapeutic approach and helping healthcare providers and patients making personalized choices amongst an increasing array of therapeutic options. Aim: To provide a comprehensive summary of the whole process of AAV‐based gene therapy from basic principles to clinical implementation through an illustrated review. Methods: The authors, with expertise in and knowledge about gene therapy for haemophilia A and B, reviewed relevant articles from PubMed database and translated them into illustrations. Results: The review is divided into eight illustrated sections providing an overview of gene therapy for haemophilia A and B from haemophilia basics and current treatment landscape, principles of the AAV‐based liver‐directed gene therapy, through exploring the efficacy and safety results of published phase III clinical trials, current and future challenges, to implementation in clinical practice, including the hub and spoke models and the patient journey. Conclusion: This illustrated review educates healthcare professionals on AAV‐based gene therapy for haemophilia A and B enabling them to further educate their peers and their patients. [ABSTRACT FROM AUTHOR]

FcRn plays a major role in regulating immune homeostasis, but it is also able to transport biologics across cellular barriers. The question of whether FcRn could be an efficient transporter of biologics across the nasal epithelial barrier is of particular interest, as it would allow a less invasive strategy for the administration of biologics in comparison to subcutaneous, intramuscular or intravenous administrations, which are often used in clinical practice. A focused systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. It was registered on the international prospective register of systematic reviews PROSPERO, which helped in identifying articles that met the inclusion criteria. Clinical and preclinical studies involving FcRn and the nasal delivery of biologics were screened, and the risk of bias was assessed across studies using the Oral Health Assessment Tool (OHAT). Among the 12 studies finally included in this systematic review (out of the 758 studies screened), 11 demonstrated efficient transcytosis of biologics through the nasal epithelium. Only three studies evaluated the potential toxicity of biologics’ intranasal delivery, and they all showed that it was safe. This systematic review confirmed that FcRn is expressed in the nasal airway and the olfactory epithelium, and that FcRn may play a role in IgG and/or IgG-derived molecule-transcytosis across the airway epithelium. However, additional research is needed to better characterize the pharmacokinetic and pharmacodynamic properties of biologics after their intranasal delivery.

Purpose: The purpose of this study was to determine the test–retest reliability of the 80s-slide-test in well-trained alpine ski racers. Methods: The sample consisted of 8 well-trained alpine ski racers (age = 17.8 [0.7] y old; height = 1.80 [0.09] m; body mass = 72.1 [9.5] kg) who performed a lab-based maximal graded test on cycle ergometer and three 80s-slide-tests in 4 separate sessions. The 80s-slide-test consisting of maximal push-offs performed for 80s on a 8-ft slide board. Oxygen uptake ( V ˙ O 2 ) and heart rate (HR) were recorded continuously. Blood lactate ([La]b) was determined immediately prerun, followed by 3 minutes postrun. Three minutes after the completion of the session, the subjects were asked to indicate their rate of perceived exertion using Borg scale ranging from 6 to 20. Total and every 10s mean push-offs number were assessed by camera. Typical errors of measurement, intraclass correlation coefficients, and smallest worthwhile change were calculated. Results: The 80s-slide-test showed strong reliability for total push-offs number, V ˙ O 2 peak , V ˙ O 2 mean , HRpeak, and HRmean. Δ[La]b, fatigue index, and the rate of perceived exertion were moderately reliable. Conclusion: The 80s-slide-test is a reliable test for well-trained alpine ski racers and can be used easily by trainers. [ABSTRACT FROM AUTHOR]

At birth, severe thrombocytopenia without context of infection should mainly suggest neonatal alloimmune thrombocytopenia (NAIT), especially in case of a platelet count below 20 GL−1. We report two cases of severe neonatal thrombocytopenia, first suspected as being NAIT. Both had a platelet count below 20 GL−1 with platelet clumps. The absence of alloantibodies and failure of platelet transfusion and intravenous immunoglobulins to improve the platelet count led to question the diagnosis and to evoke inherited bleeding disorders. Measurements of Von Willebrand factor (VWF) levels showed a marked reduction of VWF:RCo and a normal VWF:Ag, suggesting a type 2B Von Willebrand disease (VWD2B). Ristocetin-induced platelet aggregation could not be performed because of the very low platelet count. In the first case, after sequencing VWF exon 28, a heterozygous p.Leu1460Pro mutation was found consistent with VWD2B. In the second case, the genetic analysis of VWF exon 28 identified a homozygous mutation: p.Pro1337Leu confirming type VWD2B and also the p.Arg854Gln homozygous mutation in exon 20 confirming type 2N (ratio FVIII/VWF:Ag

Systemic sclerosis (SSc) is an autoimmune connective tissue disorder, characterized by multisystem involvement, vasculopathy, and fibrosis. An increased risk of malignancy is observed in SSc (including breast and lung cancers), and in a subgroup of patients with specific autoantibodies (i.e., anti-RNA polymerase III and related autoantibodies), SSc could be a paraneoplastic syndrome and might be directly related to an immune response against cancer. Herein, we reviewed the literature, focusing on the most recent articles, and shed light onto the potential relationship between cancer and scleroderma regarding temporal and immunological dimensions.

Objectives: Skin fibrosis is the hallmark of systemic sclerosis (SSc) a rare intractable disease with unmet medical need. We previously reported the anti-fibrotic potential of mesenchymal stem cells (MSCs) in a murine model of SSc. This model, based on daily intra-dermal injections of hypochlorite (HOCl) during 6 weeks, is an inducible model of the disease. Herein, we aimed at characterizing the development of skin fibrosis in HOCl-induced SSc (HOCl-SSc), and evaluating the impact of MSC infusion during the fibrogenesis process.Methods: After HOCl-SSc induction in BALB/c mice, clinical, histological and biological parameters were measured after 3 weeks (d21) and 6 weeks (d42) of HOCl challenge, and 3 weeks after HOCl discontinuation (d63). Treated-mice received infusions of 2.5 × 105 MSCs 3 weeks before sacrifice (d0, d21, d42).Results: HOCl injections induced a two-step process of fibrosis development: first, an ‘early inflammatory phase’, characterized at d21 by highly proliferative infiltrates of myofibroblasts, T-lymphocytes and macrophages. Second, a phase of ‘established matrix fibrosis’, characterized at d42 by less inflammation, but strong collagen deposition and followed by a third phase of ‘spontaneous tissue remodeling’ after HOCl discontinuation. This phase was characterized by partial fibrosis receding, due to enhanced MMP1/TIMP1 balance. MSC treatment reduced skin thickness in the three phases of fibrogenesis, exerting more specialized mechanisms: immunosuppression, abrogation of myofibroblast activation, or further enhancing tissue remodeling, depending on the injection time-point.Conclusion: HOCl-SSc mimics three fibrotic phenotypes of scleroderma, all positively impacted by MSC therapy, demonstrating the great plasticity of MSC, a promising cure for SSc.

A new trend has been swelling in the ocean of comparative mythology. Different research has been carried out using statistics to reconstruct the (pre)history of myths and mythological motifs (replicable episodes of traditional narratives) and to understand how they have evolved. The results obtained by using these different approaches converge and make it possible to intertwine numerous strands of evidence. We will try to summarize it in this paper, with special focus in the first part on the research on motifs, in the second part, on the research on different versions of a same myth. Folklore and mythology form an autonomous sphere of culture being largely independent from outer factors. The transition of folklore and mythology motifs between generations does not require material resources. Accordingly, they can be preserved during an indeterminately long period of time and this ability to be preserved can become a major asset in the study of the human past. [ABSTRACT FROM AUTHOR]

ObjectivesProperties of mesenchymal stromal/stem cells (MSCs) from systemic sclerosis (SSc) patients have been reported to be altered. MSC-based therapy may therefore rely on the use of allogeneic MSCs from healthy subjects. Here, we investigated whether heterologous MSCs could exhibit altered properties following exposure to oxidative environment of SSc sera.MethodsHuman bone marrow-derived MSCs were cultured in the presence of various sera: control human serum AB (SAB), SAB with HOCl-induced AOPPs at 400 or 1,000 µmol/L (SAB400 or SAB1000, respectively), or H2O2-induced AOPPs or SSc patient serum (PS). Proliferation, apoptosis, and senescence rates of MSCs were evaluated after 3, 6, and 10 days in culture. Reactive oxygen species and nitric oxide production were quantified at 24 h. Trilineage potential of differentiation was tested after 21 days in specific culture conditions and immunosuppressive function measured in a T lymphocyte proliferative assay.ResultsIn the presence of oxidative environment of PS, MSCs retained their proliferative potential and survived for at least the first 3 days of exposure, while the number of senescent MSCs increased at day 6 and apoptosis rate at day 10. Exposure to PS enhanced the antioxidant capacity of MSCs, notably the expression of SOD2 antioxidant gene. By contrast, the osteoblastic/adipogenic potential of MSCs was increased, whereas their immunosuppressive function was slightly reduced.DiscussionAlthough some functional properties of MSCs were affected upon culture with PS, evidence from preclinical studies and the present one suggested that MSCs can adapt to the oxidative environment and exert their therapeutic effect.

Recently our group has described a new autosomal dominant bleeding disorder characterized by very high plasma levels of soluble thrombomodulin (TM). The THBD c.1611C>A (p.Cys537X) mutation in heterozygous state was found in the propositus. This mutation leads to the synthesis of a truncated TM which has lost the last three amino-acids of the transmembrane domain and the cytoplasmic tail.We investigated the mechanism responsible for TM shedding in endothelial cells with THBD c.1611C>A mutation.Complementary DNA of TM wild type (TM-WT) was incorporated into a pcDNA3.1 vector for transient transfection in COS-1 cells. Mutagenesis was performed to create the c.1611C