Risks of Ventricular Arrhythmia and Heart Failure in Carriers of RBM20 Variants

BACKGROUND: Variants in RBM20 are reported in 2% to 6% of familial cases of dilated cardiomyopathy and may be associated with fatal ventricular arrhythmia and rapid heart failure progression. We sought to determine the risk of adverse events in RBM20 variant carriers and the impact of sex on outcomes. METHODS: Consecutive probands and relatives carrying RBM20 variants were retrospectively recruited from 12 cardiomyopathy units. The primary end point was a composite of malignant ventricular arrhythmia (MVA) and end-stage heart failure (ESHF). MVA and ESHF end points were also analyzed separately and men and women compared. Left ventricular ejection fraction (LVEF) contemporary to MVA was examined. RBM20 variant carriers with left ventricular systolic dysfunction (RBM20LVSD) were compared with variant-elusive patients with idiopathic left ventricular systolic dysfunction. RESULTS: Longitudinal follow-up data were available for 143 RBM20 variant carriers (71 men; median age, 35.5 years); 7 of 143 had an MVA event at baseline. Thirty of 136 without baseline MVA (22.0%) reached the primary end point, and 16 of 136 (11.8%) had new MVA with no significant difference between men and women (log-rank P=0.07 and P=0.98, respectively). Twenty of 143 (14.0%) developed ESHF (17 men and 3 women; log-rank P&lt;0.001). Four of 10 variant carriers with available LVEF contemporary to MVA had an LVEF &gt;35%. At 5 years, 15 of 67 (22.4%) RBM20LVSD versus 7 of 197 (3.6%) patients with idiopathic left ventricular systolic dysfunction had reached the primary end point (log-rank P&lt;0.001). RBM20 variant carriage conferred a 6.0-fold increase in risk of the primary end point. CONCLUSIONS: RBM20 variants are associated with a high risk of MVA and ESHF compared with idiopathic left ventricular systolic dysfunction. The risk of MVA in male and female RBM20 variant carriers is similar, but male sex is strongly associated with ESHF.</p

Risks of Ventricular Arrhythmia and Heart Failure in Carriers of RBM20 Variants

BACKGROUND: Variants in RBM20 are reported in 2% to 6% of familial cases of dilated cardiomyopathy and may be associated with fatal ventricular arrhythmia and rapid heart failure progression. We sought to determine the risk of adverse events in RBM20 variant carriers and the impact of sex on outcomes. METHODS: Consecutive probands and relatives carrying RBM20 variants were retrospectively recruited from 12 cardiomyopathy units. The primary end point was a composite of malignant ventricular arrhythmia (MVA) and end-stage heart failure (ESHF). MVA and ESHF end points were also analyzed separately and males and females compared. Left ventricular ejection fraction (LVEF) contemporary to MVA was examined. RBM20 variant carriers with left ventricular systolic dysfunction (RBM20LVSD) were compared with variant-elusive patients with idiopathic left ventricular systolic dysfunction. RESULTS: Longitudinal follow-up data were available for 143 RBM20 variant carriers (71 male; median age, 35.5 years); 7 of 143 had an MVA event at baseline. Thirty of 136 without baseline MVA (22.0%) reached the primary end point, and 16 of 136 (11.8%) had new MVA with no significant difference between males and females (log-rank P=0.07 and P=0.98, respectively). Twenty of 143 (14.0%) developed ESHF (17 males and 3 females; log-rank P35%. At 5 years, 15 of 67 (22.4%) RBM20LVSD versus 7 of 197 (3.6%) patients with idiopathic left ventricular systolic dysfunction had reached the primary end point (log-rank P<0.001). RBM20 variant carriage conferred a 6.0-fold increase in risk of the primary end point. CONCLUSIONS: RBM20 variants are associated with a high risk of MVA and ESHF compared with idiopathic left ventricular systolic dysfunction. The risk of MVA in male and female RBM20 variant carriers is similar, but male sex is strongly associated with ESHF

Comparing osteonecrosis clinical phenotype, timing, and risk factors in children and young adults treated for acute lymphoblastic leukemia.

To access publisher's full text version of this article click on the hyperlink belowTreatment-related osteonecrosis (ON) is a serious complication of treatment of acute lymphoblastic leukemia (ALL). This study included 1,489 patients with ALL, aged 1-45 years, treated according to the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol, using alternate-week dexamethasone during delayed intensification, with prospective registration of symptomatic ON. We aimed at comparing risk factors, timing, and clinical characteristics of ON in children and young adults. ON was diagnosed in 67 patients, yielding a 5-year cumulative incidence of 6.3%, but 28% in female adolescents. Median age at ALL diagnosis was 12.1 years and 14.9 years for females and males, respectively. At ON diagnosis, 59 patients had bone pain (91%) and 30 (46%) had multiple-joint involvement. The median interval between ALL and ON diagnosis was significantly shorter in children aged 1.0-9.9 years (0.7 years [range: 0.2-2.1]) compared with adolescents (1.8 years [range: 0.3-3.7, P < 0.001]) and adults (2.1 years [range: 0.4-5.3, P = 0.001]). Female sex was a risk factor in adolescent patients (hazard ratio [HR] = 2.1, 95% confidence interval [CI]: 1.1-4.2) but not in children aged 1.1-9.9 years (HR = 2.4, 95% CI: 0.9-6.2, P = 0.08) or adults aged 19-45 years (HR = 1.1, 95% CI: 0.3-4.0). Age above 10 years at ALL diagnosis (odds ratio [OR] = 3.7, P = 0.026) and multiple joints affected at ON diagnosis (OR = 3.4, P = 0.027) were risk factors for developing severe ON. We provide a detailed phenotype of patients with ALL with symptomatic ON, including description of risk factors and timing of ON across age groups. This awareness is essential in exploring measures to prevent development of ON.Danish Childhood Cancer Foundation Swedish Childhood Cancer Foundation Dagmar Marshalls Foundation Foundation for Danish Cancer Research Otto Christensen Foundation Axel Muusfeldts Foundatio

International Collaboration for a Sustainable Future: Faculty and Student Reflections from a Virtual Polytechnic Classroom

This paper represents a concrete reflection on the first steps in a Collaborative Online International Learning journey through the Global Polytechnic Alliance participation in Map the System. The polytechnics are in Denmark (VIA), Canada (Humber College), and New Zealand (Otago Polytechnic). Students and faculty participated in the initiative to work together strategically, based on common interests, to strengthen the participating institutions academically and globally. Three international teams were developed to participate and enter into the Map the System global competition. The teams chose a social or environmental issue that mattered to them and researched connecting elements and factors to share findings in a way that people can meaningfully learn from. This competition, and the paper, is viewed as a discovery process. In this article, we describe three stages the team went through faculty team formation, teaching and learning as well as developing student research and system maps. Through this process, we discovered key insights on creating a sense of community online, systems thinking and reflective learning process. The paper concludes with our thoughts on the unintended gifts of collaborating internationally in virtual teams

Expression of DNA signaling pathway molecules in IL2/PHA PBMCs and CD4+ T cells.

<p>(<b>A</b>) Whole cell lysates of IL2/PHA PBMCs from 2 donors were analyzed for expression of IFI16, STING, TBK1, IRF3 and β-actin by Western Blotting. (<b>B, C</b>) Whole cell lysates from IL2/PHA-treated PBMCs and CD4+ T cells were stimulated with ssDNA, dsDNA (both 2 µg/mL) or lipofactamine for 2 h of IL2/PHA PBMCs were analyzed for levels of IFI16 and cGAS by Western Blotting. Similar results were obtained with two independent donors.</p

IL2/PHA PBMCs fail to induce type I IFN responses and pro-inflammatory cytokines upon DNA transfection.

<p>(<b>A–D</b>) IL2/PHA PBMCs were transfected with HIV-derived ssDNA and dsDNA (2 µg/mL), or infected with SeV (MOI 0.5). Total RNA was isolated after 6 hours for RT-qPCR measurements of (<b>A</b>) IFNβ, (<b>B</b>) CXCL10, (<b>C</b>) ISG56, and (<b>D</b>) Viperin. (<b>E–H</b>) IL2/PHA PBMCs were transfected with ssDNA and dsDNA (2 µg/mL), or infected with SeV (MOI 0.5). Supernatants were harvested after 24 hours and analyzed for CXCL10, TNFα, MIP-1α, and IL6 protein levels. (<b>I–J</b>) PMA (100 nM) treated THP-1 cells were transfected with ssDNA and dsDNA (2 µg/mL). Total RNA was harvested after 6 hours for RT-qPCR measurements of IFNβ and CXCL10 mRNA. (<b>K</b>) Primary human monocyte-derived macrophages (MDM)s were transfected with ssDNA and dsDNA (2 µg/mL). Total RNA was harvested after 6 hours for RT-qPCR measurements of IFNβ. (<b>L</b>) Un-stimulated PBMCs were isolated and immediately transfected with ssDNA and dsDNA (2 µg/mL), or infected with SeV (MOI 0.5). Supernatants were harvested after 24 hours and analyzed for CXCL10 by ELISA. Both PCR and ELISA data are shown as means of triplicates +/− SD. Similar results were obtained in three independent experiments. Mock, Lipofectamine.</p

Transfected DNA co-localizes with the DNA sensor IFI16 in activated T cells.

<p>(<b>A, C</b>) IL2/PHA PBMCs transfected with 2 µg/mL of FITC-labeled DNA or 0.5 µM ODN2216 as indicated for 2 hours were fixed and stained with anti-IFI16 antibody and visualized by confocal microscopy. Presented cells stained positive for CD3. IFI16 is shown in red and DNA in green. (<b>B, D</b>) Percentage colocalization of cytoplasmic spots positive for IFI16 and DNA. Data is based on quantification of IFI16/DNA spots in more than 100 cells per donor in 3 different donors. Data is shown as means +/− SD. Scale bar, 5 µm.</p