Differences in the prognostic value of the electrocardiographic pattern after cardiac resynchronization therapy according to age.

OBJECTIVES: In this cohort study, we analyzed if a specific pattern in three leads of the electrocardiogram (Rs in V1, Qr in aVL, or rS in I) was associated with outcomes after cardiac resynchronization therapy (CRT) depending on age. METHODS: Patients with CRT devices were included from January 2012 to April 2019. We divided the sample into 2 groups, those with age ≥ 75 years old and those younger. The primary endpoint was a composite of all-cause death and heart failure (HF) hospitalization at 1 year. RESULTS: We included 111 patients. Patients older than 75 years (26.1%, n = 29) had a significantly higher rate of hypertension and atrial fibrillation and received less frequently optimal medical therapy. The patterns were observed in 32 (39.0%) younger patients and 11 (37.9%) older patients. Patients who presented any of them had a lower incidence of the primary endpoint in the younger group (0 vs. 14%, p = 0.029), but not in the older group (9.1 vs. 27.8%, p = 0.24). The presence of a basal QRS duration greater than 160 ms was associated with a higher rate of the primary endpoint in the elderly (50 vs. 13%, p = 0.015), but not in the younger group (16.7 vs. 7.1%, p = 0.254). CONCLUSIONS: The presence of the selected patterns after CRT is associated with a lower incidence of all-cause death and hospitalization for HF in patients younger than 75 years, but not in those older than 75 years. Conversely, baseline QRS duration was associated with worse outcomes in older patients, but not in the younger group.

Development of a 76k Alpaca (Vicugna pacos) Single Nucleotide Polymorphisms (SNPs) Microarray.

Small farm producers' sustenance depends on their alpaca herds and the production of fiber. Genetic improvement of fiber characteristics would increase their economic benefits and quality of life. The incorporation of molecular marker technology could overcome current limitations for the implementation of genetic improvement programs. Hence, the aim of this project was the generation of an alpaca single nucleotide polymorphism (SNP) microarray. A sample of 150 Huacaya alpacas from four farms, two each in Puno and Cerro de Pasco were used for SNP discovery by genotyping by sequencing (GBS). Reduced representation libraries, two per animal, were produced after DNA digestion with ApeK1 and double digestion with Pst1-Msp1. Ten alpaca genomes, sequenced at depths between 12× to 30×, and the VicPac3.1 reference genome were used for read alignments. Bioinformatics analysis discovered 76,508 SNPs included in the microarray. Candidate genes SNPs (302) for fiber quality and color are also included. The microarray SNPs cover 90.5% of the genome length with a density of about 39 ± 2.51 SNPs/Mb of DNA at an average interval of 26.45 ± 18.57 kbp. The performance was evaluated by genotyping 30 family trios and comparing them to their pedigrees, as well as comparing microarray to GBS genotypes. Concordance values of 0.93 and 0.94 for ApeK1 and Pst1-Msp1 generated SNPs were observed. Similarly, 290 fiber quality and color candidate gene SNPs were validated. Availability of this microarray will facilitate genome-wide association studies, marker-assisted selection and, in time, genomic selection.

Loss of the Immune Checkpoint CD85j/LILRB1 on Malignant Plasma Cells Contributes to Immune Escape in Multiple Myeloma.

Mechanisms of immune regulation may control proliferation of aberrant plasma cells (PCs) in patients with monoclonal gammopathy of undetermined significance (MGUS) preventing progression to active multiple myeloma (MM). We hypothesized that CD85j (LILRB1), an inhibitory immune checkpoint for B cell function, may play a role in MM pathogenesis. In this study, we report that patients with active MM had significantly lower levels of CD85j and its ligand S100A9. Decreased CD85j expression could also be detected in the premalignant condition MGUS, suggesting that loss of CD85j may be an early event promoting tumor immune escape. To gain insight into the molecular mechanisms underlying CD85j functions, we next enforced expression of CD85j in human myeloma cell lines by lentiviral transduction. Interestingly, gene expression profiling of CD85j-overexpressing cells revealed a set of downregulated genes with crucial functions in MM pathogenesis. Furthermore, in vitro functional assays demonstrated that CD85j overexpression increased susceptibility to T cell- and NK-mediated killing. Consistently, ligation of CD85j decreased the number of PCs from individuals with MGUS but not from patients with MM. In conclusion, downregulation of inhibitory immune checkpoints on malignant PCs may provide a novel mechanism of immune escape associated with myeloma pathogenesis.

The BET bromodomain inhibitor CPI203 improves lenalidomide and dexamethasone activity in in vitro and in vivo models of multiple myeloma by blockade of Ikaros and MYC signaling.

Most patients with multiple myeloma treated with current therapies, including immunomodulatory drugs, eventually develop relapsed/refractory disease. Clinical activity of lenalidomide relies on degradation of Ikaros and the consequent reduction in IRF4 expression, both required for myeloma cell survival and involved in the regulation of MYC transcription. Thus, we sought to determine the combinational effect of an MYC-interfering therapy with lenalidomide/dexamethasone. We analyzed the potential therapeutic effect of the combination of the BET bromodomain inhibitor CPI203 with the lenalidomide/dexamethasone regimen in myeloma cell lines. CPI203 exerted a dose-dependent cell growth inhibition in cell lines, indeed in lenalidomide/dexamethasone-resistant cells (median response at 0.5 µM: 65.4%), characterized by G1 cell cycle blockade and a concomitant inhibition of MYC and Ikaros signaling. These effects were potentiated by the addition of lenalidomide/dexamethasone. Results were validated in primary plasma cells from patients with multiple myeloma co-cultured with the mesenchymal stromal cell line stromaNKtert. Consistently, the drug combination evoked a 50% reduction in cell proliferation and correlated with basal Ikaros mRNA expression levels (P=0.04). Finally, in a SCID mouse xenotransplant model of myeloma, addition of CPI203 to lenalidomide/dexamethasone decreased tumor burden, evidenced by a lower glucose uptake and increase in the growth arrest marker GADD45B, with simultaneous downregulation of key transcription factors such as MYC, Ikaros and IRF4. Taken together, our data show that the combination of a BET bromodomain inhibitor with a lenalidomide-based regimen may represent a therapeutic approach to improve the response in relapsed/refractory patients with multiple myeloma, even in cases with suboptimal prior response to immunomodulatory drugs.

Early healing assessment with optical coherence tomography of everolimus-eluting stents with bioabsorbable polymer (synergy™) at 3 and 6 months after implantation.

OBJECTIVES: In this study we sought to evaluate coverage and apposition of Synergy™ stent at 3 and 6 months after implantation. BACKGROUND: The Pt-Cr everolimus-eluting stent with abluminal bioabsorbable polymer (Synergy™) is a new generation drug-eluting stent with features potentially favoring an early healing process which could make safe a shorter period of dual antiplatelet-therapy treatment. METHODS: Prospective, two-centers study enrolling patients with similar lesions treated with Synergy™ stents undergoing examination with OCT at 3 and 6 months in the respective centers. Blinded analysis was done at a core lab. Co-primary endpoints were proportion of struts with coverage and with apposition at 3 and 6 months. RESULTS: Finally, 22 patients (30 stents) in the 3 months group and 20 patients (30 stents) in the 6 months group were included. There were no significant differences between groups regarding clinical, angiographic measurements, and procedural data. The rate of strut coverage was 94.5% at 3 months and 96.6% at 6 months (P < 0.001), the rates of apposition were 93.8% and 96.2%, respectively, (P < 0.001), the proportion of uncovered but apposed struts was 2.5% and 1.9% (P = 0.03) and the proportion of uncovered and malapposed struts was 3% and 1.8%, respectively (P < 0.001). The maximal area of malapposition related with uncovered struts was 0.43 ± 0.4 mm(2) at 3 months and 0.14 ± 0.2 mm(2) at 6 months (P = 0.001). CONCLUSIONS: The everolimus-eluting stent with absorbable polymer, Synergy™, is associated to a high degree of intimal coverage and apposition at 3 months after implantation with additional increase at 6 months. © 2015 Wiley Periodicals, Inc.

Bilateral exudative retinal detachment as the first sign of relapsing acute myelogenous leukaemia.

Bilateral exudative retinal detachment is rarely seen as an ocular manifestation of acute myelogenous leukaemia. Herein, a case is described where a trans-scleral choroidal biopsy was used to diagnose relapsing acute myelogenous leukaemia when the rest of her systemic work-up was negative.