Despite the use of intensified LLT, many FH patients continue to experience high plasma LDL-C levels and, consequently, do not achieve recommended treatment targets. Type of LDL-receptor mutation, use of ezetimibe, coexistent diabetes, and ASCVD status can bear significantly on the likelihood of attaining LDL-C treatment goals.

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Objective-Heterozygous familial hypercholesterolemia (FH) is the most common premature atherosclerotic cardiovascular disease (ASCVD)-related monogenic disorder, and it is associated with ischemic heart disease.

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Monitoring for CMV-specific CMI in intermediate-risk KT recipients must be regular to reflect dynamic changes in overall immunosuppression and individual susceptibility. The early assessment at post-transplant day 15 remains particularly informative.

Stem cells must proliferate and differentiate to generate the lineages that shape mature organs; understanding these 2 processes and their interaction is one of the central themes in current biomedicine. An intriguing aspect is asymmetric division, by which 2 daughter cells with different fates are generated. Several cell fate determinants participate in asymmetric division, with the endocytic adaptor Numb as the best-known example. Here, we have explored the role of asymmetric division in thymocyte development, visualizing the differential segregation of Numb and pre-TCR in thymic precursors. Analysis of mice where Numb had been inhibited by expressing a dominant negative revealed enhanced pre-T-cell receptor (TCR) signaling and a smaller thymus. Conversely, Numb overexpression resulted in loss of asymmetric division and a larger thymus. The conclusion is that Numb determines the levels of pre-TCR signaling in dividing thymocytes and, ultimately, the size of the pool from which mature T lymphocytes are selected. IntroductionThe mammalian thymus contains different cell types originated from initially equivalent precursors that undergo several rounds of division. To ensure correct numbers of mature lineage-specific cells in adult organs, precursors divide asymmetrically, generating 2 sister cells with different fates. 1,2 One of the "cell fate determinants" asymmetrically segregated is Numb, a plasma membrane-associated protein that contains a phosphotyrosine binding (PTB) domain and antagonizes Notch signaling. Numb function was first described in Drosophila sensory organ precursors, 3 where loss of Numb resulted in both daughter cells adopting the fate of the cell that normally inherits Notch, whereas the opposite was caused by Numb overexpression. [4][5][6] In mammalians, asymmetric division has been studied most extensively during neurogenesis. 7 Deletion of Numb and its homologue Numblike resulted in loss of neural progenitors and block of neurogenesis, 8 as a result of progenitor overdifferentiation and death of young neurons. In other systems, Numb binds to integrins 9 and Src family kinases, 10 mediates receptor internalization, 11,12 and participates in clathrin-dependent endosomal association. 13 Thus, Numb plays multiple and important roles in development and signaling; however, little is known about its role in the thymus.T lymphocytes develop from precursors that undergo a series of cell fate decisions, resulting in differentiation into single positive (SP) thymocytes, the immediate precursors of fully functional CD4 and CD8 T lymphocytes. 14,15 The initial CD4 Ϫ CD8 Ϫ double negative (DN) stages are influenced by signals from the pre-T-cell receptor (TCR) [16][17][18] and Notch. 19,20 Only DN thymocytes receiving proper pre-TCR and Notch signals are able to evolve into the CD4 ϩ CD8 ϩ double positive (DP) ␣␤ lineage stage. Pre-TCR internalization and degradation is very important for correct signaling. [21][22][23] As a consequence of pre-TCR signaling, DN thymocytes proliferate, enabling normal nu...

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The QuantiFERON-CMV (QF) assay measures cell-mediated immunity against cytomegalovirus (CMV-CMI), which is particularly useful in individuals susceptible to CMV infection such as transplant patients. A positive QF result identifies patients that are better protected against CMV infection. However, the significance of a negative QF result in CMV-seropositive individuals needs to be clarified. CMV-CMI was analyzed in healthy subjects using the QF assay, and, in parallel, the Flow-cytometric Assay of Specific Cell-mediated Immune response in Activated whole blood (FASCIA). FASCIA assay measures T-cell proliferation using CMV lysate as stimulus whereas QF assay use a mix of peptides. A total of 93 healthy volunteers were enrolled, and 13/71 CMV-seropositive individuals (18.3%) showed humoral/ cellular discordance using QF assay (CMV+ QF−). Interestingly, with FASCIA assay CD4+ and CD8+ T-cell proliferations were lower in CMV+ QF− than in CMV+ QF+ individuals. Furthermore, CMV+ QF− volunteers had a lower level of anti-CMV IgG than CMV+ QF+ subjects. Discordant CMV+ QF− volunteers can be defined as low responder individuals since they show lower CMV-specific humoral and cellular immune responses in comparison to CMV+ QF+ individuals. Immune discordance shows the high heterogeneity of immunity to CMV in healthy subjects.In the last years, a variety of assays have been developed to measure cell-mediated immunity against cytomegalovirus (CMV-CMI), where the basic principle is the CMV-specific stimulation of T cells for 6-24 hours in cell culture 1,2 . These techniques have been shown to be particularly useful in individuals such as transplant patients who are susceptible to CMV infection, since they identify who is better protected against CMV infection after transplantation, as has been reported in international guidelines on the management of CMV in solid organ or stem cell transplantation 3,4 . Specifically, the detection of CMV-CMI at pretransplant or posttransplant using QuantiFERON-CMV (QF), ELISpot or intracellular cytokine staining has been associated with a lower risk of CMV infection, not only in observational studies 5-9 .Although most individuals show an agreement between CMV-serostatus and CMV-CMI, some of them have a discordance. Therefore, there are CMV-seropositive individuals without CMV-CMI, as well as CMV-seronegative individuals with protective CMV-CMI. Discordant individuals have been reported in both transplant patients and healthy virus carriers 8-12 .The QuantiFERON-CMV is an in vitro assay that measures CMV-CMI by quantifying IFNG released by CD8+ T cells after stimulation with a pool of HLA-restricted CMV peptides 13 . In some observational studies carried out in our group in solid organ transplant patients we found that 20-25% of CMV-seropositive transplant open Scientific RepoRtS | (2020) 10:7194 | https://doi.org/10.1038/s41598-020-64133-x www.nature.com/scientificreports www.nature.com/scientificreports/ candidates lacked CMV-CMI response using the QF assay, and they showed a higher risk of p...