Seismic risk assessment of a new RC-framed skin technology for integrated retrofitting interventions on existing buildings

A RC-framed-skin technology for the integrated seismic and thermal retrofitting interventions on existing buildings, recently proposed by some of the authors, is thoroughly investigated. By means of numerical analyses, its effectiveness and suitability within the framework of seismic risk class assessment is proved. The system is composed of a RC-framed structure with an external reinforced plaster layer that does not offer a structural contribution to the capacity of the system in ultimate conditions, but which can be effective by increasing the lateral stiffness in serviceability conditions. The system is realized from the outside of the existing building so guaranteeing limited invasiveness of the intervention and preventing the interruption of the building use by their occupants. An existing RC building, representative of a typical example of the Italian building stock, is analyzed as a case study, and its seismic risk class upgrade, obtained by the proposed strengthening intervention, is assessed by non-linear static analysis. The numerical models are developed within the OpenSees framework. The Expected Annual Loss (EAL) parameter, together with the Life Safety Index (LS-I), are chosen as synthetic measures that include both aspects related to Ultimate Limit state (ULS) and Serviceability Limit State (SLS) conditions. The risk class accounting for or disregarding the contribution of the external reinforced plaster are finally compared

A Novel Mutation in GP1BB Reveals the Role of the Cytoplasmic Domain of GPIbβ in the Pathophysiology of Bernard-Soulier Syndrome and GPIb-IX Complex Assembly

Bernard-Soulier syndrome (BSS) is an autosomal-recessive bleeding disorder caused by biallelic variants in the GP1BA, GP1BB, and GP9 genes encoding the subunits GPIbα, GPIbβ, and GPIX of the GPIb-IX complex. Pathogenic variants usually affect the extracellular or transmembrane domains of the receptor subunits. We investigated a family with BSS caused by the homozygous c.528_550del (p.Arg177Serfs*124) variant in GP1BB, which is the first mutation ever identified that affects the cytoplasmic domain of GPIbβ. The loss of the intracytoplasmic tail of GPIbβ results in a mild form of BSS, characterized by only a moderate reduction of the GPIb-IX complex expression and mild or absent bleeding tendency. The variant induces a decrease of the total platelet expression of GPIbβ; however, all of the mutant subunit expressed in platelets is correctly assembled into the GPIb-IX complex in the plasma membrane, indicating that the cytoplasmic domain of GPIbβ is not involved in assembly and trafficking of the GPIb-IX receptor. Finally, the c.528_550del mutation exerts a dominant effect and causes mild macrothrombocytopenia in heterozygous individuals, as also demonstrated by the investigation of a second unrelated pedigree. The study of this novel GP1BB variant provides new information on pathophysiology of BSS and the assembly mechanisms of the GPIb-IX receptor

ACTN1‐related thrombocytopenia: Homozygosity for an ACTN1 variant results in a more severe phenotype

ACTN1-related thrombocytopenia is a rare disorder caused by heterozygous variants in the ACTN1 gene characterized by macrothrombocytopenia and mild bleeding tendency. We describe for the first time two patients affected with ACTN1-RT caused by a homozygous variant in ACTN1 (c.982G>A) with mild heart valve defects unexplained by any other genetic variants investigated by WES. Within the reported family, the homozygous sisters have moderate thrombocytopenia and marked platelet macrocytosis with giant platelets, revealing a more severe haematological phenotype compared to their heterozygous relatives and highlighting a significant effect of allelic burden on platelet size. Moreover, we hypothesize that some ACTN1 variants, especially when present in the homozygous state, may also contribute to the cardiac abnormalities

Autosomal dominant macrothrombocytopenia in Italy is most frequently a type of heterozygous Bernard-Soulier syndrome

A form of autosomal dominant macrothrombocytopenia is characterized by mild or no clinical symptoms, normal platelet function, and normal megakaryocyte count. Because this condition has so far received little attention, patients are subject to misdiagnosis and inappropriate therapy. To identify the molecular basis of this disease, 12 Italian families were studied by linkage analysis and mutation screening. Flow cytometry evaluations of platelet membrane glycoproteins (GPs) were also performed. Linkage analysis in 2 large families localized the gene to chromosome 17p, in an interval containing an excellent candidate, the GPIbα gene. GPIbα, together with other proteins, constitutes the plasma von Willebrand factor (vWF) receptor, which is altered in Bernard-Soulier syndrome (BSS). In 6 of 12 families, a heterozygous Ala156Val missense substitution was identified. Platelet membrane GP studies were performed in 10 patients. Eight were distinguished by a reduction of GPs comparable to that found in a BSS heterozygous condition, whereas the other 2, without the Ala156Val mutation, had a normal content of platelet GPs. In conclusion, the current study provides evidence that most (10 of 12) patients with an original diagnosis of autosomal dominant macrothrombocytopenia shared clinical and molecular features with the heterozygous BSS phenotype. The remaining 2 affected subjects represented patients with "true" autosomal dominant macrothrombocytopenia; the GPIb/IX/V complex was normally distributed on the surface of their platelets. Thus, the diagnosis of heterozygous BSS must always be suspected in patients with inherited thrombocytopenia and platelet macrocytosis

The Use of a Scenario-Based Nominal Group Technique to Assess P/CVE Programs: Development and Pilot Testing of a Toolkit

Preventing and countering violent extremism (P/CVE) requires coordination among multiple agencies, stakeholders and systems. The complexity of this task (compounded by the variety of P/CVE programming around the world) creates a  challenge for those hoping to develop these initiatives. The purpose of this project was to develop a replicable process and corresponding toolkit to engage multiple stakeholders in consensus building around the efficacy and improvement of nascent, developing or mature systems-level P/CVE programs. As a method, we adapted the process of nominal group technique (NGT), a structured-brainstorming tool that provides an orderly procedure for obtaining qualitative and ranked information from heterogenous participant pools. The technique we developed is based on a case-study approach (“scenario”) which we then tested in three countries (USA, Sweden, and North Macedonia) with existing P/CVE initiatives at different stages of development. We conducted scenario-based NGT sessions in each location and then systematically analyzed the results using iterative qualitative coding based on a common framework. Results were analyzed to achieve consensus on the most common system-level challenges and system-level functions, necessary to overcome those challenges, in each location. Practitioners in each local jurisdiction were then able to utilize the results derived from the NGT for their own purposes, such as advocacy to policy makers, strategic regional P/CVE planning, and ongoing stakeholder engagement. Acknowledgments: This project was funded by the NATO Science for Peace and Security Programme under the award entitled "Evaluation Support for CVE at the Local Level" SPS.MYPG5556, the Swedish Contingency Agency (MSB), and the U.S. Department of Homeland Security (DHS), Science and Technology Directorate (Cooperative Agreement Number: 2015-ST-108-FRG005). The content of this manuscript as well as the views and discussions expressed are solely those of the authors and do not necessarily represent the official views of any of the above institutions, nor does mention of trade names, commercial practices, or organizations imply endorsement by the U.S. government

Congenital amegakaryocytic thrombocytopenia: clinical and biological consequences of five novel mutations

BACKGROUND AND OBJECTIVES: Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, autosomal recessive disorder induced by mutations of the gene coding for thrombopoietin (TPO) receptor (c-MPL). Patients initially present with isolated thrombocytopenia that subsequently progresses into pancytopenia. Although the mechanisms leading to aplasia are unknown, the age of onset has been reported to depend on the severity of the c-MPL functional defect. To improve our knowledge in this field, we studied clinical and biological features of five new patients. DESIGN AND METHODS: We diagnosed five CAMT patients, identified c-MPL mutations, including five novel alterations and investigated relationships between mutations and their clinical-biological consequences. RESULTS: In all cases, platelet c-MPL and bone marrow colonies were reduced, while serum TPO levels were elevated. We also documented that the percentage of bone marrow cells expressing tumor necrosis factor-a and interferon-g was increased during pancytopenia as compared to in controls, suggesting that, as in other bone marrow failure diseases, these inhibitory cytokines contributed to the pancytopenia. Contrary to previously published data, we found no evidence of correlations between different types of mutations and the clinical course. INTERPRETATION AND CONCLUSIONS: These results suggest that therapies, such as hematopoietic stem cell transplantation, which are potentially curative although associated with a risk of treatment-related mortality, should not be postponed even in those CAMT patients whose c-MPL mutations might predict residual activity of the TPO receptor