OGT controls mammalian cell viability by regulating the proteasome/mTOR/ mitochondrial axis.

O-GlcNAc transferase (OGT) modifies serine and threonine residues on nuclear and cytosolic proteins with O-linked N-acetylglucosamine (GlcNAc). OGT is essential for mammalian cell viability, but the underlying mechanisms are still enigmatic. We performed a genome-wide CRISPR-Cas9 screen in mouse embryonic stem cells (mESCs) to identify candidates whose depletion rescued the block in cell proliferation induced by OGT deficiency. We show that the block in cell proliferation in OGT-deficient cells stems from mitochondrial dysfunction secondary to mTOR (mechanistic target of rapamycin) hyperactivation. In normal cells, OGT maintains low mTOR activity and mitochondrial fitness through suppression of proteasome activity; in the absence of OGT, increased proteasome activity results in increased steady-state amino acid levels, which in turn promote mTOR lysosomal translocation and activation, and increased oxidative phosphorylation. mTOR activation in OGT-deficient mESCs was confirmed by an independent phospho-proteomic screen. Our study highlights a unique series of events whereby OGT regulates the proteasome/ mTOR/ mitochondrial axis in a manner that maintains homeostasis of intracellular amino acid levels, mitochondrial fitness, and cell viability. A similar mechanism operates in CD8+ T cells, indicating its generality across mammalian cell types. Manipulating OGT activity may have therapeutic potential in diseases in which this signaling pathway is impaired.

Angiographic characteristics of patients with STEMI and COVID-19: Insights from NACMI registry.

BACKGROUND: To date, there has been no independent core lab angiographic analysis of patients with COVID-19 and STEMI. The study characterized the angiographic parameters of patients with COVID-19 and STEMI. METHODS: Angiograms of patients with COVID-19 and STEMI from the North American COVID-19 Myocardial Infarction (NACMI) Registry were sent to a Core Laboratory in Vancouver, Canada. Culprit lesion(s), Thrombolysis In Myocardial Infarction (TIMI) flow, Thrombus Grade Burden (TGB), and percutaneous coronary intervention (PCI) outcome were assessed. RESULTS: From 234 patients, 74% had one culprit lesion, 14% had multiple culprits and 12% had no culprit identified. Multivessel thrombotic disease and multivessel CAD were found in 27% and 53% of patients, respectively. Stent thrombosis accounted for 12% of the presentations and occurred in 55% of patients with previous coronary stents. Of the 182 who underwent PCI, 60 (33%) had unsuccessful PCI due to post-PCI TIMI flow <3 (43/60), residual high thrombus burden (41/60) and/or thrombus related complications (27/60). In-hospital mortality for successful, partially successful, and unsuccessful PCI was 14%, 13%, and 27%, respectively. Unsuccessful PCI was associated with increased risk of in-hospital mortality (risk ratio [RR] 1.96; 95% CI: 1.05-3.66, P = .03); in the adjusted model this estimate was attenuated (RR: 1.24; 95% CI: 0.65-2.34, P = .51). CONCLUSION: In patients with COVID-19 and STEMI, thrombus burden was pervasive with notable rates of multivessel thrombotic disease and stent thrombosis. Post-PCI, persistent thrombus and sub-optimal TIMI 3 flow rates led to one-third of the PCI's being unsuccessful, which decreased over time but remained an important predictor of in-hospital mortality.

Giant valley-Zeeman coupling in the surface layer of an intercalated transition metal dichalcogenide.

Spin-valley locking is ubiquitous among transition metal dichalcogenides with local or global inversion asymmetry, in turn stabilizing properties such as Ising superconductivity, and opening routes towards 'valleytronics'. The underlying valley-spin splitting is set by spin-orbit coupling but can be tuned via the application of external magnetic fields or through proximity coupling. However, only modest changes have been realized to date. Here, we investigate the electronic structure of the V-intercalated transition metal dichalcogenide V1/3NbS2 using microscopic-area spatially resolved and angle-resolved photoemission spectroscopy. Our measurements and corresponding density functional theory calculations reveal that the bulk magnetic order induces a giant valley-selective Ising coupling exceeding 50 meV in the surface NbS2 layer, equivalent to application of a ~250 T magnetic field. This energy scale is of comparable magnitude to the intrinsic spin-orbit splittings, and indicates how coupling of local magnetic moments to itinerant states of a transition metal dichalcogenide monolayer provides a powerful route to controlling their valley-spin splittings.

Novel Antibodies for the Simple and Efficient Enrichment of Native O-GlcNAc Modified Peptides.

Antibodies against posttranslational modifications (PTMs) such as lysine acetylation, ubiquitin remnants, or phosphotyrosine have resulted in significant advances in our understanding of the fundamental roles of these PTMs in biology. However, the roles of a number of PTMs remain largely unexplored due to the lack of robust enrichment reagents. The addition of N-acetylglucosamine to serine and threonine residues (O-GlcNAc) by the O-GlcNAc transferase (OGT) is a PTM implicated in numerous biological processes and disease states but with limited techniques for its study. Here, we evaluate a new mixture of anti-O-GlcNAc monoclonal antibodies for the immunoprecipitation of native O-GlcNAcylated peptides from cells and tissues. The anti-O-GlcNAc antibodies display good sensitivity and high specificity toward O-GlcNAc-modified peptides and do not recognize O-GalNAc or GlcNAc in extended glycans. Applying this antibody-based enrichment strategy to synaptosomes from mouse brain tissue samples, we identified over 1300 unique O-GlcNAc-modified peptides and over 1000 sites using just a fraction of sample preparation and instrument time required in other landmark investigations of O-GlcNAcylation. Our rapid and robust method greatly simplifies the analysis of O-GlcNAc signaling and will help to elucidate the role of this challenging PTM in health and disease.

Peripheral arterial disease and hypertension.

PURPOSE OF REVIEW: Hypertension (HTN) is a well known risk factor for atherosclerosis and peripheral arterial disease (PAD). PAD affects more than 250 million people globally and is associated with worse clinical outcomes. Although multiple studies have been performed to evaluate treatment of HTN in patients with PAD, blood pressure management in this high-risk cohort remains poor. RECENT FINDINGS: There has been conflicting evidence regarding blood pressure goals in PAD with some recent studies showing adverse outcomes with low blood pressure in this patient population. Current guidelines, however, continue to recommend treatment goals in PAD patients similar to patients without PAD. To date, no single antihypertensive drug class has shown a clear benefit in PAD population over other antihypertensive drug classes. SUMMARY: Prospective randomized trials enrolling PAD patients are required that can shed light on optimum blood pressure target and also distinguish between different antihypertensive drugs in terms of reducing adverse outcomes.

Cerebral protection during percutaneous intervention for left ventricular assist device outflow graft obstruction.

BACKGROUND: Left ventricular assist devices (LVAD) outflow graft obstruction is an uncommon complication but carries significant morbidity and mortality. Here we provide a case series of patients with LVAD intrinsic outflow graft obstruction who are deemed to be a high surgical risk for pump exchange and, therefore, underwent percutaneous intervention with the concomitant use of neuroprotective device-Sentinel cerebral protection system (CPS) (Boston Scientific) to prevent embolic stroke. METHODS: We retrospectively analyzed patients who underwent LVAD placement in our institution and developed LVAD outflow graft obstruction. The diagnosis of LVAD outflow graft obstruction was confirmed by utilizing various cardiac imaging modalities such as echocardiography and/or computed tomography angiography. All patients were treated with percutaneous intervention and a catheter-based CPS. RESULTS: From a total of 501 LVAD implants in our institute, 6 (1.2%) patients with LVAD outflow graft obstruction who underwent percutaneous treatment were included; 4 patients with HeartMate-III LVAD, 1 patient with HeartMate-II LVAD, and 1 patient with HeartWare (HVAD). The median age of patients was 56.5 years at the time of LVAD implantation. The median time from the LVAD implantation to the episode of LVAD outflow obstruction was 1343 days. Utilization of Sentinel CPS resulted in the capture and removal of thrombus/debris in all patients. CONCLUSIONS: Percutaneous intervention of LVAD outflow graft obstruction is less invasive than surgical pump exchange and an acceptable alternative in properly selected patients. In our experience, utilization of a catheter-based CPS can help in reducing the incidence of periprocedural embolic events.

SCAI publications committee manual of standard operating procedures.

Evidence-based recommendations for clinical practice are intended to help health care providers and patients make decisions, minimize inappropriate practice variation, promote effective resource use, improve clinical outcomes, and direct future research. The Society for Cardiovascular Angiography and Interventions (SCAI) has been engaged in the creation and dissemination of clinical guidance documents since the 1990s. These documents are a cornerstone of the society's education, advocacy, and quality improvement initiatives. The publications committee is charged with oversight of SCAI's clinical documents program and has created this manual of standard operating procedures to ensure consistency, methodological rigor, and transparency in the development and endorsement of the society's documents. The manual is intended for use by the publications committee, document writing groups, external collaborators, SCAI representatives, peer reviewers, and anyone seeking information about the SCAI documents program.

Household food insufficiency, health status and emergency healthcare utilisation among children with and without special healthcare needs.

OBJECTIVE: To compare exposure to household food insufficiency and the relationship between household food insufficiency and both health status and emergency healthcare utilisation among children with and without special healthcare needs (SHCN). DESIGN: Analysing pooled data from the 2016-2017 iterations of the National Survey of Children's Health, we conducted multivariate logistic regressions on household food insufficiency, health status and emergency healthcare utilisation. We assessed interactions between household food insufficiency and children's SHCN status in our models of health status and utilisation. SETTING: United States. PARTICIPANTS: Parents of a nationally representative sample of non-institutionalised children (aged 0-17 years). RESULTS: Children with SHCN were more likely to experience household food insufficiency (70 v. 56 %), non-excellent health status (67 v. 28 %) and emergency healthcare utilisation (32 v. 18 %) than other children. Household food insufficiency was associated with 37 % (children with SHCN) and 19 % (children without SHCN) reductions in the likelihood of having excellent health. Household food insufficiency was associated with a roughly equal (16-19 %) increase in the likelihood of emergency department utilisation across groups. CONCLUSIONS: Compared with other children, children with SHCN have an elevated risk of exposure to household food insufficiency and experiencing greater reductions in health status when exposed.

Understanding the Role of Past Health Care Discrimination in Help-Seeking and Shared Decision-Making for Depression Treatment Preferences.

As a part of a larger, mixed-methods research study, we conducted semi-structured interviews with 21 adults with depressive symptoms to understand the role that past health care discrimination plays in shaping help-seeking for depression treatment and receiving preferred treatment modalities. We recruited to achieve heterogeneity of racial/ethnic backgrounds and history of health care discrimination in our participant sample. Participants were Hispanic/Latino (n = 4), non-Hispanic/Latino Black (n = 8), or non-Hispanic/Latino White (n = 9). Twelve reported health care discrimination due to race/ethnicity, language, perceived social class, and/or mental health diagnosis. Health care discrimination exacerbated barriers to initiating and continuing depression treatment among patients from diverse backgrounds or with stigmatized mental health conditions. Treatment preferences emerged as fluid and shaped by shared decisions made within a trustworthy patient-provider relationship. However, patients who had experienced health care discrimination faced greater challenges to forming trusting relationships with providers and thus engaging in shared decision-making processes.

Food insecurity patterns before and after initial receipt of Supplemental Security Income.

OBJECTIVE: To assess patterns of food insecurity before and after initial receipt of Supplemental Security Income (SSI) benefits. DESIGN: We analysed data from a nationally representative sample. We estimated two difference-in-difference models comparing food insecurity patterns among eventual SSI recipients with patterns among eligible non-recipients during two time frames. The first model assessed changes in food insecurity immediately before SSI benefits were first received and the second model assessed changes in food insecurity after programme entry. SETTING: 2008 panel of the Survey of Income and Program Participation.ParticipantsNon-institutionalized population of the USA. RESULTS: The percentage of eventual SSI recipients experiencing food insecurity rose from 18 to 30 % in the year before programme entry, compared with a change from 17 to 18 % for eligible non-recipients. Adjusting for sociodemographic covariates, the difference-in-difference estimator for this comparison was statistically significant (P=0·01). Additionally, the percentage of recipients experiencing food insecurity fell from 28 % in the year before programme entry to 16 % in the year after entry, compared with a change from 16 to 17 % for eligible non-recipients. Adjusting for sociodemographic covariates, the difference-in-difference estimator for this comparison was marginally significant (P=0·07). CONCLUSIONS: Food insecurity rises prior to SSI entry but may be alleviated by programme benefits. Greater nutritional supports for SSI applicants awaiting decisions may reduce the burden of food insecurity in this population and improve health outcomes.

Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting in Treatment of Unprotected Left Main Stenosis.

PURPOSE OF REVIEW: This article reviews the latest data on unprotected left main (ULM) percutaneous coronary intervention (PCI) versus coronary artery bypass graft (CABG) surgery, with a focus on the NOBLE and EXCEL trials. RECENT FINDINGS: In EXCEL trial, the primary endpoint at 3 years was 15.4% in the PCI group and 14.7% in the CABG group (p = 0.02 for non-inferiority of PCI versus CABG). In NOBLE, the primary endpoint at 5 years was 28% and 18% for PCI and CABG, respectively (HR 1.51, CI 1.13-2.0, which did not meet the criteria for non-inferiority of PCI to CABG; p for superiority of CABG was 0.0044). Higher repeat revascularization and non-procedural myocardial infarction were noted in PCI group but there was no difference in all-cause or cardiac mortality between the two groups. A heart team approach with appropriate patient selection, careful assessment of LM lesions, and meticulous procedural technique makes PCI a valid alternative to CABG for ULM stenosis.

Inpatient Medicaid Usage and Expenditure Patterns After Changes in Supplemental Nutrition Assistance Program Benefit Levels.

INTRODUCTION: Food insecurity worsens health outcomes and is associated with increased health care usage and expenditures. The Supplemental Nutrition Assistance Program (SNAP) reduces but does not eliminate recipients' food insecurity. We sought to determine whether inpatient Medicaid usage and expenditure patterns responded to an April 2009 increase in SNAP benefit levels and a subsequent November 2013 decrease. METHODS: Interrupted time series models estimated responses to the 2009 and 2013 SNAP changes in the Medicaid population, compared responses between Medicaid and Medicare recipients, and compared responses between Medicaid recipients with different likelihoods of having a disability. Analyses used 2006 through 2014 Healthcare Cost and Utilization Project National (previously Nationwide) Inpatient Sample data. RESULTS: After the 2009 SNAP increase, Medicaid admission growth fell nationally from 0.80 to 0.35 percentage points per month (a difference of -0.45; 95% CI, -0.72 to -0.19), adjusting for enrollment. After the 2013 SNAP decrease, admission growth rose to 2.42 percentage points per month (a difference of 2.07; 95% CI, 0.68 to 3.46). Inflation-adjusted monthly Medicaid expenditures followed similar patterns and were associated with $26.5 billion (in 2006 dollars) in reduced expenditures over the 55 months of the SNAP increase, and $6.4 billion (in 2006 dollars) in additional expenditures over the first 14 months after the SNAP decrease. Effects were elevated for Medicaid compared with Medicare recipients and among people with a high likelihood of having a disability. CONCLUSION: Although alternative causal explanations warrant consideration, changes in SNAP benefit levels were associated with changes in inpatient Medicaid usage and cost patterns.

Selumetinib with and without erlotinib in KRAS mutant and KRAS wild-type advanced nonsmall-cell lung cancer.

BACKGROUND: KRAS mutations in NSCLC are associated with a lack of response to epidermal growth factor receptor inhibitors. Selumetinib (AZD6244; ARRY-142886) is an oral selective MEK kinase inhibitor of the Ras/Raf/MEK/ERK pathway. PATIENTS AND METHODS: Advanced nonsmall-cell lung cancer (NSCLC) patients failing one to two prior regimens underwent KRAS profiling. KRAS wild-type patients were randomized to erlotinib (150 mg daily) or a combination of selumetinib (150 mg daily) with erlotinib (100 mg daily). KRAS mutant patients were randomized to selumetinib (75 mg b.i.d.) or the combination. The primary end points were progression-free survival (PFS) for the KRAS wild-type cohort and objective response rate (ORR) for the KRAS mutant cohort. Biomarker studies of ERK phosphorylation and immune subsets were carried out. RESULTS: From March 2010 to May 2013, 89 patients were screened; 41 KRAS mutant and 38 KRAS wild-type patients were enrolled. Median PFS in the KRAS wild-type arm was 2.4 months [95% confidence interval (CI) 1.3-3.7] for erlotinib alone and 2.1 months (95% CI 1.8-5.1) for the combination. The ORR in the KRAS mutant group was 0% (95% CI 0.0% to 33.6%) for selumetinib alone and 10% (95% CI 2.1% to 26.3%) for the combination. Combination therapy resulted in increased toxicities, requiring dose reductions (56%) and discontinuation (8%). Programmed cell death-1 expression on regulatory T cells (Tregs), Tim-3 on CD8+ T cells and Th17 levels were associated with PFS and overall survival in patients receiving selumetinib. CONCLUSIONS: This study failed to show improvement in ORR or PFS with combination therapy of selumetinib and erlotinib over monotherapy in KRAS mutant and KRAS wild-type advanced NSCLC. The association of immune subsets and immune checkpoint receptor expression with selumetinib may warrant further studies.

Late breaking trials of 2015 in structural heart disease and peripheral artery disease: Commentary covering ACC, EuroPCR, SCAI, TCT, VIVA, ESC, and AHA.

With the large number of late breaking clinical trials presented at major meetings, it is often difficult to stay current with advances in interventional cardiology. Therefore, the SCAI Publications Committee summarizes and provides editorial commentary on the most important structural heart and peripheral artery disease late-breaking trials from 2015. © 2016 Wiley Periodicals, Inc.

SCAI/SVM expert consensus statement on carotid stenting: Training and credentialing for carotid stenting.

Carotid artery stenting (CAS) has become an integral part of the therapeutic armamentarium offered by cardiovascular medicine programs for the prevention of stroke. The purpose of this expert consensus statement is to provide physician training and credentialing guidance to facilitate the safe and effective incorporation of CAS into clinical practice within these programs. Since publication of the 2005 Clinical Competence Statement on Carotid Stenting, there has been substantial device innovation, publication of numerous clinical trials and observational studies, accumulation of extensive real-world clinical experience and widespread participation in robust national quality improvement initiatives [5]. Collectively, these advances have led to substantial evolution in the selection of appropriate patients, as well as in the cognitive, technical and clinical skills required to perform safe and effective CAS. Herein, we summarize published guidelines, describe training pathways, outline elements of competency, offer strategies for tracking outcomes, specify facility, equipment and personnel requirements, and propose criteria for maintenance of CAS competency.

Commentary on highlighted late breaking trials in interventional cardiology at ESC, VIVA, TCT, and AHA 2013.

With the plethora of clinical trials, it is difficult for busy interventional cardiologists to stay up to date. Therefore, the SCAI publications committee concisely summarizes and provides editorial commentary on the most important trials from recent, large international meetings. The intent is to provide this summary every six months to allow quick assimilation of trial results into interventional practice. © 2014 Wiley Periodicals, Inc.

Commentary on late breaking trials in interventional cardiology at ESC, VIVA, TCT, AHA (Fall 2012), and ACC 2013.

With the plethora of clinical trials, it is difficult for busy interventional cardiologists to stay up to date. Therefore, the Society for Cardiovascular Angiography and Interventions (SCAI) publications committee concisely summarized and provided editorial commentary on the most important trials from recent, large international meetings. The intent is to provide this summary every six months to allow quick assimilation of trial results into interventional practice.