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Abstract An important epigenetic component of tyrosine kinase signaling is the phosphorylation of histones, and epigenetic readers, writers, and erasers. Phosphorylation of protein arginine methyltransferases (PRMTs), have been shown to enhance and impair their enzymatic activity. In this study, we show that the hyperactivation of Janus kinase 2 (JAK2) by the V617F mutation phosphorylates tyrosine residues (Y149 and Y334) in coactivator-associated arginine methyltransferase 1 (CARM1), an important target in hematologic malignancies, increasing its methyltransferase activity and altering its target specificity. While non-phosphorylatable CARM1 methylates some established substrates (e.g. BAF155 and PABP1), only phospho-CARM1 methylates the RUNX1 transcription factor, on R223 and R319. Furthermore, cells expressing non-phosphorylatable CARM1 have impaired cell-cycle progression and increased apoptosis, compared to cells expressing phosphorylatable, wild-type CARM1, with reduced expression of genes associated with G2/M cell cycle progression and anti-apoptosis. The presence of the JAK2-V617F mutant kinase renders acute myeloid leukemia (AML) cells less sensitive to CARM1 inhibition, and we show that the dual targeting of JAK2 and CARM1 is more effective than monotherapy in AML cells expressing phospho-CARM1. Thus, the phosphorylation of CARM1 by hyperactivated JAK2 regulates its methyltransferase activity, helps select its substrates, and is required for the maximal proliferation of malignant myeloid cells.

Background: Baseline left ventricular diastolic dysfunction (LVDD) is associated with poor health status in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement (TAVR), but health status improvement after TAVR appears similar across all grades of LVDD. Here, we aim to examine the relationship between changes in LVDD severity and health status outcomes following TAVR. Methods: Patients who underwent TAVR and had evaluable LVDD at both baseline and 1 year in the PARTNER (Placement of Aortic Transcatheter Valves) 2 SAPIEN 3 registries and PARTNER 3 trial were analyzed. LVDD grade was evaluated using echocardiography core lab data and an adapted definition of American Society of Echocardiography guidelines. Health status was assessed using the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score. The association between ΔLVDD severity and ΔKCCQ-OS was examined using linear regression models adjusted for baseline KCCQ-OS. Results: Of 1100 patients, 724 (65.8%), 283 (25.7%), and 93 (8.5%) had grade 0/1, 2, and 3 LVDD at baseline, respectively. At 1 year, LVDD severity was unchanged in 790 (71.8%) patients, improved in 189 (17.2%), and worsened in 121 (11.0%). Among 376 patients with baseline grade 2 or 3 LVDD, 50.3% had improvement in LVDD. In the overall cohort, KCCQ-OS score improved by 21.9 points at 1 year. There was a statistically significant association between change in LVDD severity (improved, unchanged, and worsened) and ΔKCCQ-OS at 1 year (p = 0.007). Conclusions: Change in LVDD grade was associated with change in health status 1 year following TAVR.

In this paper, Chebyshev operational matrices collocation technique is proposed for solution of variable order derivative within the fractional time-delay diffusion equation. The beginning of this approach is based on the construction of the solution using the shifted Chebyshev polynomials with unknown coefficients. After that, we performed the Newton–Cotes nodal points, the Chebyshev polynomials operational matrices, and the collocation method for calculating the unknown coefficients. According to the described technique, we get an algebraic system of nonlinear equations which can be solved easily by using Newton’s iterative method. The efficiency and applicability of suggested approach are illustrated by some tested examples.

During emergency hematopoiesis, hematopoietic stem cells (HSCs) rapidly proliferate to produce myeloid and lymphoid effector cells, a response that is critical against infection or tissue injury. If unresolved, this process leads to sustained inflammation, which can cause life-threatening diseases and cancer. Here, we identify a role of double PHD fingers 2 (DPF2) in modulating inflammation. DPF2 is a defining subunit of the hematopoiesis-specific BAF (SWI/SNF) chromatin-remodeling complex, and it is mutated in multiple cancers and neurological disorders. We uncovered that hematopoiesis-specific Dpf2-KO mice developed leukopenia, severe anemia, and lethal systemic inflammation characterized by histiocytic and fibrotic tissue infiltration resembling a clinical hyperinflammatory state. Dpf2 loss impaired the polarization of macrophages responsible for tissue repair, induced the unrestrained activation of Th cells, and generated an emergency-like state of HSC hyperproliferation and myeloid cell–biased differentiation. Mechanistically, Dpf2 deficiency resulted in the loss of the BAF catalytic subunit BRG1 from nuclear factor erythroid 2-like 2–controlled (NRF2-controlled) enhancers, impairing the antioxidant and antiinflammatory transcriptional response needed to modulate inflammation. Finally, pharmacological reactivation of NRF2 suppressed the inflammation-mediated phenotypes and lethality of Dpf2Δ/Δ mice. Our work establishes an essential role of the DPF2-BAF complex in licensing NRF2-dependent gene expression in HSCs and immune effector cells to prevent chronic inflammation.

The homotopy perturbation method is extend to derive the approximate solution of the variable order fractional partial differential equations with time delay. The variable order fractional derivative is taken in the Caputo sense. An approximation formula of the Caputo derivative of fractional variable order is presented in terms of standard (integer order) derivatives only. Then the original problem will be transformed into a systems of partial differential equations with delay. By employing the homotopy perturbation method the explicit approximate solutions are found. The error and convergence analysis of the homotopy perturbation method has been discussed for the applicability of the method. The absolute errors and the approximate solutions are presented graphically and by tables at the values of various variable fractional order. From the results of the illustrated examples, we can Judge that the homotopy perturbation method is very effective, and simple accelerates the rapid convergence of the solution.

The use of an ozonized bubble column reactor (OBCR) in wastewater treatment is advantageous due to its efficient mixing and mass transfer characteristics. Among all high-performance features, the ozonation reaction in a BCR undergoes a low dissolution of O3 in the reactor with a limited reaction rate. In this study, the ozonation reaction of phenol in an OBCR was tested using a ZnO nanocatalyst and alumina balls as packing material. Three concentrations of O3 were evaluated (i.e., 10, 15, and 20 ppm), and 20 ppm was found to be the optimum concentration for phenol degradation. Also, two doses (i.e., 0.05 and 0.1 g/L) of ZnO nanocatalysts were applied in the reaction mixture, with the optimal dose found to be 0.1 g/L. Accordingly, three phenol concentrations were investigated in the OBCR (i.e., 15, 20, and 25 ppm) using four treatment methods (i.e., O3 alone, O3/Al2O3, O3/ZnO nanocatalyst, and O3/Al2O3/ZnO nanocatalyst). At a contact time of 60 min and phenol concentration of 15 ppm, the removal rate was 66.2, 73.1, 74.5, and 86.8% for each treatment method, respectively. The treatment experiment that applied the O3/Al2O3/ZnO nanocatalyst produced the highest phenol conversion into CO2 and H2O in the shortest contact time for all phenol concentrations. Thus, the OBCR employed with a ZnO nanocatalyst plus packing material is a promising technology for the rapid and active removal of phenol because it enhances the number of hydroxyl radicals (•OH) generated, which ultimately increases the oxidation activity in the OBCR. Also, the results showed efficient flow characteristics in the OBCR, with channeling problems averted due to appropriate gas movement resulting from the use of packing materials. Finally, it was found that the ozonation process in an OBCR is an efficient method for phenol conversion with good economic feasibility.

Background. Despite an association between operator volumes and procedural success, there remains an incomplete understanding of the contemporary utilization and procedural volumes for mitral valve transcatheter edge-to-edge repair (MTEER). We aimed to identify annual operator procedural volumes, temporal trends, and geographic variability for MTEER among Medicare patients in the United States (US). Methods. We queried the National Medicare Provider Utilization and Payment Database for a CPT code (33418) specific for MitraClip device from 2015 through 2019. We analyzed annual operator procedural volumes and incidence and identified longitudinal and geographic trends in MTEER utilization. Results. From 2015 through 2019, a total of 27,034 MTEER procedures were performed among Medicare patients in the US. The nationwide incidence increased from 6.2 per 100,000 patients in 2015 to 23.8 per 100,000 patients in 2019, a 283% increase over the study period (Ptrend

Profile deck steel sheets are used in composite deck slabs. These sheets are standard in dimensions and shapes besides they are supplied with embossments and indentations. Such sheets are not available in Iraqi markets nowadays therefore people used another type of sheets which are corrugated without embossments or indentations in very wide range. This study covers the use of such sheets in composite slabs as decks instead of standard profiled steel sheets. The study comprises testing slabs of dimensions 0.9 × 2.5 m reinforced by steel fabric mesh and rested on corrugated sheets. Two types of shear spans are selected shorter and longer to study the longitudinal shear force transmitted due to the applied loads according to the Eurocode 4. The shorter shear spans are 600, 500 and 400 mm while longer one is 800, 750 and 700 mm. The study extended to support the requirements of design equation of the Eurocode by shear bond method also known as m–k method. The evaluated values of m and k are 0.094 and 65 respectively. The result of k which plays a very important role in shear transfer is small compared to what available in literature, therefore it is recommended to make use of shear connectors in such construction or any else method.

Background Hospitalization rates after transcatheter aortic valve replacement (TAVR) remain high, given the age and comorbidities of patients undergoing TAVR. To better understand the impact of TAVR on hospitalization, we sought to compare hospitalization rates before and after TAVR and to examine if underlying patient comorbidities are associated with a differential effect of TAVR on hospitalizations. Methods and Results We used the Nationwide Readmissions Database to identify patients who underwent TAVR. As Nationwide Readmissions Database data do not cross over calendar years, we limited our index admission to hospitalizations during April to September of each calendar year to allow 90 days of observation before and after TAVRs. We calculated the daily risk of all‐cause hospitalization and used a mixed‐effects logistic regression model to explore interactions between patient characteristics, TAVR, and hospitalization risk. Among 39 249 patients who underwent TAVR in 2014 to 2017 (median age, 82 years [interquartile range, 76–87 years]; 45.7% women), 32.0% had at least one hospitalization in the 90 days before TAVR compared with 23.2% in the 90 days post‐TAVR (relative reduction, 27.5%; P

Cyber-physical systems (CPSs) were envisaged as a way to manipulate the objects in the physical world through computer intelligence. This is usually done by providing a communication bridge between actuation and computing elements. This sought after control is hampered not only by the unavoidable certainty found in the physical world but also by the limitations of contemporary communication networks. These limitations hamper fine-grained control of elements that may be separated by large-scale distances. In this regard, soft computing is an emerging paradigm that can help to manage the unreliability of CPS by using techniques, including fuzzy systems, neural networks, evolutionary computation, probabilistic reasoning, and rough sets. We present a comprehensive contemporary review of soft computing techniques for CPS dependability modeling, analysis, and improvement. This paper provides an overview of CPS applications, explores the foundations of dependability engineering, and highlights the potential role of soft computing techniques for CPS dependability with various case studies while also identifying common pitfalls and future directions. In addition, this paper provides a comprehensive survey of the use of various soft computing techniques for making CPS dependable. This paper is timely due to the increasingly central role that CPSs are beginning to play in modern societies and the need to leverage all the relevant methodologies and tools (such as those provided by soft computing) for the development of highly dependable CPS.

Transcatheter mitral valve repair with MitraClip is a novel, intricate therapy for mitral regurgitation that improves survival and quality of life. Similar to other medical procedures, there is a relationship between procedural experience and clinical outcomes. MitraClip results and the efficiency and safety of the procedure all improved with increasing experience at both the institutional and operator level in two large studies from the Society of Thoracic Surgeons and American College of Cardiology Transcatheter Valve Therapy Registry. Patient selection was also found to have a significant role in procedure success. The old adage of “See one, do one, teach one” does not necessarily apply to complex interventions, such as MitraClip, given that the learning curve does not appear to plateau even as operators approach a 150-case experience.

The Internet of Things (IoT) is an emerging field consisting of Internet-based globally connected network architecture. A subset of IoT is the Internet of Healthcare Things (IoHT) that consists of smart healthcare devices having significant importance in monitoring, processing, storing, and transmitting sensitive information. It is experiencing novel challenges regarding data privacy protection. This article discusses different components of IoHT and categorizes various healthcare devices based on their functionality and deployment. This article highlights the possible points and reasons for data leakage, such as conflicts in laws, the use of sub-standard devices, lack of awareness, and the non-availability of dedicated local law enforcement agencies. This article draws attention to the escalating demand for a suitable regulatory framework and analyzes compliance problems of IoHT devices concerning healthcare data privacy and protection regulations. Furthermore, the article provides some recommendations to improve the security and privacy of IoHT implementation.

Summary: Protein arginine methyltransferase 5 (PRMT5) is overexpressed in many cancer types and is a promising therapeutic target for several of them, including leukemia and lymphoma. However, we and others have reported that PRMT5 is essential for normal physiology. This dependence may become dose limiting in a therapeutic setting, warranting the search for combinatorial approaches. Here, we report that PRMT5 depletion or inhibition impairs homologous recombination (HR) DNA repair, leading to DNA-damage accumulation, p53 activation, cell-cycle arrest, and cell death. PRMT5 symmetrically dimethylates histone and non-histone substrates, including several components of the RNA splicing machinery. We find that PRMT5 depletion or inhibition induces aberrant splicing of the multifunctional histone-modifying and DNA-repair factor TIP60/KAT5, which selectively affects its lysine acetyltransferase activity and leads to impaired HR. As HR deficiency sensitizes cells to PARP inhibitors, we demonstrate here that PRMT5 and PARP inhibitors have synergistic effects on acute myeloid leukemia cells. : Hamard et al. show that PRMT5 regulates DNA-repair efficiency in hematopoietic cells by controlling the alternative splicing of key histone modifying and DNA-repair proteins, including TIP60. PRMT5 depletion or inhibition leads to a defect in DNA-repair pathway choice, which may be exploited therapeutically to target acute leukemia cells. Keywords: hematopoiesis, acute myeloid leukemia, DNA damage and repair, homologous recombination, histone post-translational modifications acetylation, methylation, alternative splicing, PRMT5, PRMT5 inhibitor, Tip60/KAT5, 53BP1, PARP inhibitor

Background Smoking is a significant risk factor for aortic stenosis but its impact on clinical and health status outcomes after transcatheter aortic valve replacement (TAVR) has not been described. Methods and Results Patients (n=72 165) undergoing TAVR at 457 US sites in the STS/ACC TVT (Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy) Registry between November 2011 and June 2016 were categorized at the time of TAVR as current/recent smokers versus prior/nonsmokers. A series of multivariable models examined the association between smoking status and outcomes, including 1‐year mortality, rehospitalization, mean gradient, and health status (measured by the 12‐item Kansas City Cardiomyopathy Questionnaire–Overall Summary Score [KCCQ‐OS]) and in‐hospital outcomes. A total of 4063 patients (5.6%) were smokers. Smokers presented for TAVR at a younger age (75 [68–81] years versus 83 [77–88] years) but with a greater burden of cardiovascular and lung disease. In adjusted models, smoking was associated with lower in‐hospital mortality (relative risk, 0.74; 95% CI, 0.62–0.89 [P=0.001]) but not with in‐hospital stroke/transient ischemic attack or myocardial infarction. Smoking status had no association with postdischarge mortality, stroke, myocardial infarction, or heart failure (HF) but was associated with slightly lower 1‐year KCCQ‐OS scores (2.4‐point lower KCCQ‐OS; 95% CI, −4.6 to −0.2 [P=0.031]) and higher mean aortic valve gradients (11.1 versus 10.2 mm Hg, P

Necroptosis is a lytic programmed cell death mediated by the RIPK1-RIPK3-MLKL pathway. The loss of Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) expression and necroptotic potential have been previously reported in several cancer cell lines; however, the extent of this loss across cancer types, as well as its mutational drivers, were unknown. Here, we show that RIPK3 expression loss occurs progressively during tumor growth both in patient tumor biopsies and tumor xenograft models. Using a cell-based necroptosis sensitivity screen of 941 cancer cell lines, we find that escape from necroptosis is prevalent across cancer types, with an incidence rate of 83%. Genome-wide bioinformatics analysis of this differential necroptosis sensitivity data in the context of differential gene expression and mutation data across the cell lines identified various factors that correlate with resistance to necroptosis and loss of RIPK3 expression, including oncogenes BRAF and AXL. Inhibition of these oncogenes can rescue the RIPK3 expression loss and regain of necroptosis sensitivity. This genome-wide analysis also identifies that the loss of RIPK3 expression is the primary factor correlating with escape from necroptosis. Thus, we conclude that necroptosis resistance of cancer cells is common and is oncogene driven, suggesting that escape from necroptosis could be a potential hallmark of cancer, similar to escape from apoptosis.

Glioblastoma multiforme (GBM) is the most malignant primary adult brain tumor. The current standard of care is surgical resection, radiation, and chemotherapy treatment, which extends life in most cases. Unfortunately, tumor recurrence is nearly universal and patients with recurrent glioblastoma typically survive

Sudden cardiac arrest is a major cause of death predominantly caused by ventricular tachyarrhythmia in patients with coronary artery disease. Despite advancements in resuscitation care, the rate of survival after cardiac arrest remains low. There is a growing body of observational data suggesting early coronary angiography reduces delay to revascularization and may improve outcomes. Most survivors present comatose, and neurologic outcome is uncertain; therefore it is often challenging to identify patients who will benefit from early coronary angiography. Several variables and risk scores that predict a favorable neurologic outcome have been identified. The rationale and current evidence for early angiography are reviewed, and a suggested approach to the selection of patients is presented.

During emergency hematopoiesis, hematopoietic stem cells (HSCs) rapidly proliferate to produce myeloid and lymphoid effector cells, a response that is critical against infection or tissue injury. If unresolved, this process leads to sustained inflammation, which can cause life-threatening diseases and cancer. Here, we identify a role of double PHD fingers 2 (DPF2) in modulating inflammation. DPF2 is a defining subunit of the hematopoiesis-specific BAF (SWI/SNF) chromatin-remodeling complex, and it is mutated in multiple cancers and neurological disorders. We uncovered that hematopoiesis-specific Dpf2-KO mice developed leukopenia, severe anemia, and lethal systemic inflammation characterized by histiocytic and fibrotic tissue infiltration resembling a clinical hyperinflammatory state. Dpf2 loss impaired the polarization of macrophages responsible for tissue repair, induced the unrestrained activation of Th cells, and generated an emergency-like state of HSC hyperproliferation and myeloid cell-biased differentiation. Mechanistically, Dpf2 deficiency resulted in the loss of the BAF catalytic subunit BRG1 from nuclear factor erythroid 2-like 2-controlled (NRF2-controlled) enhancers, impairing the antioxidant and antiinflammatory transcriptional response needed to modulate inflammation. Finally, pharmacological reactivation of NRF2 suppressed the inflammation-mediated phenotypes and lethality of Dpf2Δ/Δ mice. Our work establishes an essential role of the DPF2-BAF complex in licensing NRF2-dependent gene expression in HSCs and immune effector cells to prevent chronic inflammation.

ABSTRACT The biocide triclosan is used in many personal care products, including toothpastes, soaps, clothing, and medical equipment. Consequently, it is present as a contaminant in the environment and has been detected in some human fluids, including serum, urine, and milk. Staphylococcus aureus is an opportunistic pathogen that colonizes the noses and throats of approximately 30% of the population. Colonization with S. aureus is known to be a risk factor for several types of infection. Here we demonstrate that triclosan is commonly found in the nasal secretions of healthy adults and the presence of triclosan trends positively with nasal colonization by S. aureus. We demonstrate that triclosan can promote the binding of S. aureus to host proteins such as collagen, fibronectin, and keratin, as well as inanimate surfaces such as plastic and glass. Lastly, triclosan-exposed rats are more susceptible to nasal colonization with S. aureus. These data reveal a novel factor that influences the ability of S. aureus to bind surfaces and alters S. aureus nasal colonization. IMPORTANCE Triclosan has been used as a biocide for over 40 years, but the broader effects that it has on the human microbiome have not been investigated. We demonstrate that triclosan is present in nasal secretions of a large portion of a test population and its presence correlates with Staphylococcus aureus nasal colonization. Triclosan also promotes the binding of S. aureus to human proteins and increases the susceptibility of rats to nasal colonization by S. aureus. These findings are significant because S. aureus colonization is a known risk factor for the development of several types of infections. Our data demonstrate the unintended consequences of unregulated triclosan use and contribute to the growing body of research demonstrating inadvertent effects of triclosan on the environment and human health.

In this review of literature, the light will be concentrated on the local drugs delivery systems for treating the periodontal diseases. Principles, types, advantages and indications of each type will be discussed in this paper.

Staphylococcus aureus is an opportunistic pathogen that colonizes the skin and mucosal surfaces of mammals. Persistent staphylococcal infections often involve surface-associated communities called biofilms. Here we report the discovery of a novel extracellular fibril structure that promotes S. aureus biofilm integrity. Biochemical and genetic analysis has revealed that these fibers have amyloid-like properties and consist of small peptides called phenol soluble modulins (PSMs). Mutants unable to produce PSMs were susceptible to biofilm disassembly by matrix degrading enzymes and mechanical stress. Previous work has associated PSMs with biofilm disassembly, and we present data showing that soluble PSM peptides disperse biofilms while polymerized peptides do not. This work suggests the PSMs' aggregation into amyloid fibers modulates their biological activity and role in biofilms.

To mount an effective immune response against infectious pathogens or tissue injury, hematopoietic stem cells (HSCs) increase their proliferation and production of myeloid cells, including macrophages, which destroy the pathogens and repair the damaged tissue. Proper resolution of inflammation is essential to restore hematopoietic homeostasis, as unrestrained inflammation can result in life-threatening pathologies such as sepsis, autoimmune disorders and cancer. The molecular mechanisms that control the resolution of inflammation, and how these contribute to disease phenotypes, are poorly understood. BAF (SWI/SNF) complexes are ATPase dependent chromatin-remodeling complexes that play fundamental roles in transcription. BAF complexes use the energy of ATP to modulate the accessibility of transcription factors to DNA and thus, orchestrate the gene expression programs that control proliferation and cellular identity. Genes encoding for BAF subunits are frequently mutated in cancer and developmental disorders. In hematopoietic malignancies, loss-of-function mutations and low expression of specific BAF subunits have been reported in patients with anemia and bone marrow failure. Work from our lab previously demonstrated that the hematopoietic-specific BAF complex subunit Dpf2 cooperates with the transcription factor Runx1 to regulate myeloid differentiation. Based on these studies, we generated a hematopoietic-specific Dpf2 knock-out mouse model and found that mice lacking Dpf2 develop pancytopenia, anemia and an uncontrolled inflammatory response that results in early death. Dpf2-/- peripheral blood samples showed dysplastic features including increased number of polychromatophilic blood cells and Howell-Jolly bodies in erythrocytes. Histopathological analyses revealed the presence of fibrosis and prominent infiltration of histiocytes in multiple organs, including lungs, liver and spleen. Detailed chemical profiling of plasma showed increased levels of multiple pro-inflammatory cytokines, indicative of systemic inflammation. Flow cytometry analyses and Mass cytometry profiling further revealed an expansion of myeloid lineages, specifically monocytes and macrophages, concomitant with severe defects in lymphoid and erythroid differentiation. We also found that Dpf2-/-HSCs had increased serial re-plating capacity and a marked myeloid differentiation bias. To identify the transcription factor networks underlying these phenotypes, we performed RNAseq and ATACseq on control and Dpf2-/- HSCs. Gene Set Enrichment Analyses indicated that Dpf2-/- HSCs have extensive gene expression alterations in immune signaling and interferon response pathways, as well as leukocyte and erythroid differentiation. We also found that Dpf2 loss results in pronounced changes in expression and genomic accessibility of specific transcription factors that control macrophage differentiation and proliferation. Together, our mechanistic studies support a model whereby the absence of Dpf2 results in misregulation of the transcription factor networks that establish macrophage cell identity, leading to a marked increase in macrophage infiltrations and shortened survival of the mice. Treatment of the Dpf2-/-mice with clodronate-containing liposomes, which deplete macrophages from bone marrow and spleen, prolonged survival of the mice. Our work uncovers a novel role of Dpf2 in restraining inflammatory responses by controlling macrophage proliferation and function. Moreover, we propose that, in addition to their tumor suppressive roles in cancer, BAF complexes may have a central role in the prevention of immunopathologies. Disclosures Kadoch: Foghorn Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Other: Scientific founder, fiduciary board of directors member, scientific advisory board member, shareholder, and consultant for Foghorn Therapeutics (Cambridge, MA). . Vega:NCI: Research Funding.

Outcomes of mitral transcatheter edge-to-edge repair (MTEER) in patients with secondary mitral regurgitation (sMR) and preserved left ventricular ejection fraction (LVEF) are uncertain. This study sought to describe outcomes of MTEER for sMR with preserved LVEF. Using the STS/ACC TVT (Society of Thoracic Surgeons–American College of Cardiology Transcatheter Valve Therapy) Registry, we evaluated the risk-adjusted outcomes of MTEER for sMR with LVEF >50% by the severity of residual mitral regurgitation (MR), and we compared these outcomes to patients undergoing MTEER for sMR with LVEF of 20% to 50%. Among 12,083 patients, LVEF was >50% in 3,011 (24.9%) and 20% to 50% in 9,072 (75.1%). Technical success, in-hospital complications, the 1-year death rate, and the 1-year Kansas City Cardiomyopathy Questionnaire score were similar in patients with LVEF >50% vs LVEF of 20% to 50%. The 1-year adjusted risk of heart failure hospitalization was lower in patients with LVEF >50% vs LVEF of 20% to 50% (adjusted HR: 0.81; 95% CI: 0.68-0.97; P = 0.02). Among patients with LVEF >50%, residual MR was ≤ mild in 76.0% and moderate in 19.0%. Compared with ≤ mild MR, moderate residual MR was associated with increased 1-year risks of death (adjusted HR: 1.46; 95% CI: 1.01-2.10; P = 0.04) and heart failure hospitalization (adjusted HR: 1.82; 95% CI: 1.32-2.52; P < 0.001). At 1 year, the KCCQ score improved in patients with LVEF >50% treated with MTEER (residual MR grade ≤ mild, 28.7 ± 26.8; moderate MR, 25.7 ± 27.2; > moderate MR, 21.6 ± 12.0; all P < 0.05). In patients with sMR and preserved LVEF, MTEER was associated with a high rate of technical success, a low rate of complications, and large improvements in health status. [Display omitted] [ABSTRACT FROM AUTHOR]

During emergency hematopoiesis, hematopoietic stem cells (HSCs) rapidly proliferate to produce myeloid and lymphoid effector cells, a response that is critical against infection or tissue injury. If unresolved, this process leads to sustained inflammation, which can cause life-threatening diseases and cancer. Here, we identify a role of double PHD fingers 2 (DPF2) in modulating inflammation. DPF2 is a defining subunit of the hematopoiesis-specific BAF (SWI/SNF) chromatin- remodeling complex, and it is mutated in multiple cancers and neurological disorders. We uncovered that hematopoiesis-specific Dpf2-KO mice developed leukopenia, severe anemia, and lethal systemic inflammation characterized by histiocytic and fibrotic tissue infiltration resembling a clinical hyperinflammatory state. Dpf2 loss impaired the polarization of macrophages responsible for tissue repair, induced the unrestrained activation of Th cells, and generated an emergency- like state of HSC hyperproliferation and myeloid cell-biased differentiation. Mechanistically, Dpf2 deficiency resulted in the loss of the BAF catalytic subunit BRG1 from nuclear factor erythroid 2-like 2- controlled (NRF2-controlled) enhancers, impairing the antioxidant and antiinflammatory transcriptional response needed to modulate inflammation. Finally, pharmacological reactivation of NRF2 suppressed the inflammation-mediated phenotypes and lethality of [Dpf2.sup.[DELTA]/DELTA]] mice. Our work establishes an essential role of the DPF2-BAF complex in licensing NRF2-dependent gene expression in HSCs and immune effector cells to prevent chronic inflammation., Introduction In response to tissue injury, blood loss, or infection, hematopoietic stem cells (HSCs) exit quiescence, giving rise to highly proliferative progenitor cells, myeloid cells, and subtypes of T cells [...]