Device Failure in Bicuspid Aortic Stenosis Following Transcatheter Aortic Valve Implantation

Recent studies showed the favorable outcomes of transcatheter aortic valve implantation (TAVI) in patients with bicuspid aortic valve (BAV) stenosis. However, data on the rela-tion between BAV morphology and optimal transcatheter heart valve (THV) selection are limited. This study sought to evaluate the determinants of device performance in patients with BAV who underwent TAVI. Consecutive patients with BAV who under-went TAVI with the SAPIEN 3 from multicenters were evaluated. Outcomes were the incidence and predictors of device failure. Device failure was defined as peak aortic velocity > 3.0 m/s, mean pressure gradient > 20 mm Hg, moderate or severe paravalvular leakage and/or procedure mortality. A total of 187 patients with BAV were identified, aged 77 years, and 38.0% were women. A total of 37 patients (19.8%) were treated with 23-mm valve, 58 (31.0%) with 26-mm valve, and 92 (49.2%) with 29-mm valve. Predis -charge echocardiogram demonstrated 37 patients (19.8%) with device failure. BAV with excessive leaflet calcification plus calcified raphe (EC-BAV) (OR 16.7, 95% CI 1.99 to 39.6) and smaller THV (OR 4.41, 95% CI 1.43 to 13.6) were independently associated with increased risk of device failure. In addition, 4.0%, 5.1%, and 11.1% of device fail-ures were observed in patients without EC-BAV who underwent TAVI with 23-, 26-and 29-mm THV (p = 0.47), respectively, and 91.7%, 31.6% and 23.2% in those with EC-BAV, respectively (p < 0.001). In conclusion, EC-BAV morphology was the major deter-minant of a device failure after TAVI. Moreover, TAVI in patients with EC-BAV requir-ing small SAPIEN 3 could be challenging. Further data on device and treatment selection in patients with BAV are still warranted. (C) 2022 The Author(s). Published by Elsevier Inc.Peer reviewe

Impact of Mild Paravalvular Regurgitation on Long- Term Clinical Outcomes After Transcatheter Aortic Valve Implantation

The impact of mild paravalvular regurgitation (PVR) after transcatheter aortic valve implantation (TAVI) remains controversial. We evaluated the impact of mild PVR after TAVI on long-term clinical outcomes. We included patients who underwent TAVI for severe symptomatic aortic stenosis between December 2008 and June 2019 at 2 interna-tional centers and compared all-cause death between the group with mild PVR (group 1) and the group with none or trace PVR (group 2). PVR was categorized using a 3-class grading scheme, and patients with PVR >= moderate and those who were lost to follow-up were excluded. This retrospective analysis included 1,404 patients (mean age 81.7 +/- 6.5 years, 58.0% women). Three hundred fifty eight patients (25.5%) were classified into group 1 and 1,046 patients (74.5%) into group 2. At baseline, group 1 was older and had a lower body mass index, worse co-morbidities, and more severe aortic stenosis. To account for these differences, propensity score matching was performed, resulting in 332 matched pairs. Within these matched groups, during a mean follow-up of 3.2 years, group 1 had a significantly lower survival rate at 5 years (group 1: 62.0% vs group 2: 68.0%, log-rank p = 0.029, hazard ratio: 1.41 [95% confidence interval: 1.04 to 1.91]). In the matched cohort, patients with mild PVR had a significant 1.4-fold increased risk of mortality at 5 years after TAVI compared with those with none or trace PVR. Further studies with more patients are needed to evaluate the impact of longer-term outcomes.(c) 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) (Am J Cardiol 2023;191:14-22)Peer reviewe

Microarray analysis of promoter methylation in lung cancers

Aberrant DNA methylation is an important event in carcinogenesis. Of the various regions of a gene that can be methylated in cancers, the promoter is the most important for the regulation of gene expression. Here, we describe a microarray analysis of DNA methylation in the promoter regions of genes using a newly developed promoter-associated methylated DNA amplification DNA chip (PMAD). For each sample, methylated Hpa II-resistant DNA fragments and Msp I-cleaved (unmethylated + methylated) DNA fragments were amplified and labeled with Cy3 and Cy5 respectively, then hybridized to a microarray containing the promoters of 288 cancer-related genes. Signals from Hpa II-resistant (methylated) DNA (Cy3) were normalized to signals from Msp I-cleaved (unmethylated + methylated) DNA fragments (Cy5). Normalized signals from lung cancer cell lines were compared to signals from normal lung cells. About 10.9% of the cancer-related genes were hypermethylated in lung cancer cell lines. Notably, HIC1, IRF7, ASC, RIPK3, RASSF1A, FABP3, PRKCDBP, and PAX3 genes were hypermethylated in most lung cancer cell lines examined. The expression profiles of these genes correlated to the methylation profiles of the genes, indicating that the microarray analysis of DNA methylation in the promoter region of the genes is convenient for epigenetic study. Further analysis of primary tumors indicated that the frequency of hypermethylation was high for ASC (82%) and PAX3 (86%) in all tumor types, and high for RIPK3 in small cell carcinoma (57%). This demonstrates that our PMAD method is effective at finding epigenetic changes during cancer

Genome-wide profiling of promoter methylation in human

DNA methylation in the promoter region of a gene is associated with a loss of that gene's expression and plays an important role in gene silencing. The inactivation of tumor-suppressor genes by aberrant methylation in the promoter region is well recognized in carcinogenesis. However, there has been little study in this area when it comes to genome-wide profiling of the promoter methylation. Here, we developed a genome-wide profiling method called Microarray-based Integrated Analysis of Methylation by Isoschizomers to analyse the DNA methylation of promoter regions of 8091 human genes. With this method, resistance to both the methylation-sensitive restriction enzyme HpaII and the methylation-insensitive isoschizomer MspI was compared between samples by using a microarray with promoter regions of the 8091 genes. The reliability of the difference in HpaII resistance was judged using the difference in MspI resistance. We demonstrated the utility of this method by finding epigenetic mutations in cancer. Aberrant hypermethylation is known to inactivate tumour suppressor genes. Using this method, we found that frequency of the aberrant promoter hypermethylation in cancer is higher than previously hypothesized. Aberrant hypomethylation is known to induce activation of oncogenes in cancer. Genome-wide analysis of hypomethylated promoter sequences in cancer demonstrated low CG/GC ratio of these sequences, suggesting that CpG-poor genes are sensitive to demethylation activity in cancer

Pharmacogenetic Modulation of Orexin Neurons Alters Sleep/Wakefulness States in Mice

Hypothalamic neurons expressing neuropeptide orexins are critically involved in the control of sleep and wakefulness. Although the activity of orexin neurons is thought to be influenced by various neuronal input as well as humoral factors, the direct consequences of changes in the activity of these neurons in an intact animal are largely unknown. We therefore examined the effects of orexin neuron-specific pharmacogenetic modulation in vivo by a new method called the Designer Receptors Exclusively Activated by Designer Drugs approach (DREADD). Using this system, we successfully activated and suppressed orexin neurons as measured by Fos staining. EEG and EMG recordings suggested that excitation of orexin neurons significantly increased the amount of time spent in wakefulness and decreased both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep times. Inhibition of orexin neurons decreased wakefulness time and increased NREM sleep time. These findings clearly show that changes in the activity of orexin neurons can alter the behavioral state of animals and also validate this novel approach for manipulating neuronal activity in awake, freely-moving animals

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Large-scale exome-wide association analysis identifies loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3 UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases