Publications by authors named "Evan H Whitehead"

6 Publications

  • Page 1 of 1

Central Venous Pressure and Clinical Outcomes During Left-Sided Mechanical Support for Acute Myocardial Infarction and Cardiogenic Shock.

Front Cardiovasc Med 2020 28;7:155. Epub 2020 Aug 28.

Tufts Medical Center, Cardiovascular Center for Research and Innovation, Boston, MA, United States.

Right ventricular failure (RVF) is associated with increased mortality among patients receiving left ventricular mechanical circulatory support (LV-MCS) for cardiogenic shock and requires prompt recognition and management. Increased central venous pressure (CVP) is an indicator of potential RVF. We studied whether elevated CVP during LV-MCS for acute myocardial infarction complicated by cardiogenic shock is associated with higher mortality. Between January 2014 and June 2019, we analyzed hemodynamic parameters during Impella LV-MCS from 28 centers in the United States participating in the global, prospective catheter-based ventricular assist device (cVAD) study. A total of 132 patients with a documented CVP measurement while on Impella left-sided support for cardiogenic shock were identified. CVP was significantly higher among patients who died in the hospital (14.0 vs. 11.7 mmHg, = 0.014), and a CVP >12 identified patients at significantly higher risk for in-hospital mortality (65 vs. 45%, = 0.02). CVP remained significantly associated with in-hospital mortality even after adjustment in a multivariable model (adjusted OR 1.10 [95% CI 1.02-1.19] per 1 mmHg increase). LV-MCS suction events were non-significantly more frequent among patients with high vs. low CVP (62.11 vs. 7.14 events, = 0.067). CVP is a single, readily accessible hemodynamic parameter which predicts a higher rate of short-term mortality and may identify subclinical RVF in patients receiving LV-MCS for cardiogenic shock.
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http://dx.doi.org/10.3389/fcvm.2020.00155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485579PMC
August 2020

The science of safety: complications associated with the use of mechanical circulatory support in cardiogenic shock and best practices to maximize safety.

F1000Res 2020 29;9. Epub 2020 Jul 29.

Division of Cardiology, Detroit Medical Center/Wayne State University School of Medicine, Detroit, MI, USA.

Acute mechanical circulatory support (MCS) devices are widely used in cardiogenic shock (CS) despite a lack of high-quality clinical evidence to guide their use. Multiple devices exist across a spectrum from modest to complete support, and each is associated with unique risks. In this review, we summarize existing data on complications associated with the three most widely used acute MCS platforms: the intra-aortic balloon pump (IABP), Impella systems, and veno-arterial extracorporeal membrane oxygenation (VA-ECMO). We review evidence from available randomized trials and highlight challenges comparing complication rates from case series and comparative observational studies where a lack of granular data precludes appropriate matching of patients by CS severity. We further offer a series of best practices to help shock practitioners minimize the risk of MCS-associated complications and ensure the best possible outcomes for patients.
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http://dx.doi.org/10.12688/f1000research.25518.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391013PMC
October 2020

A Comprehensive, CRISPR-based Functional Analysis of Essential Genes in Bacteria.

Cell 2016 Jun 26;165(6):1493-1506. Epub 2016 May 26.

Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address:

Essential gene functions underpin the core reactions required for cell viability, but their contributions and relationships are poorly studied in vivo. Using CRISPR interference, we created knockdowns of every essential gene in Bacillus subtilis and probed their phenotypes. Our high-confidence essential gene network, established using chemical genomics, showed extensive interconnections among distantly related processes and identified modes of action for uncharacterized antibiotics. Importantly, mild knockdown of essential gene functions significantly reduced stationary-phase survival without affecting maximal growth rate, suggesting that essential protein levels are set to maximize outgrowth from stationary phase. Finally, high-throughput microscopy indicated that cell morphology is relatively insensitive to mild knockdown but profoundly affected by depletion of gene function, revealing intimate connections between cell growth and shape. Our results provide a framework for systematic investigation of essential gene functions in vivo broadly applicable to diverse microorganisms and amenable to comparative analysis.
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http://dx.doi.org/10.1016/j.cell.2016.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4894308PMC
June 2016

Engineering complex synthetic transcriptional programs with CRISPR RNA scaffolds.

Cell 2015 Jan 18;160(1-2):339-50. Epub 2014 Dec 18.

Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA 94158, USA; UCSF Center for Systems and Synthetic Biology, University of California San Francisco, San Francisco, CA 94158, USA; California Institute for Quantitative Biomedical Research, San Francisco, CA 94158, USA. Electronic address:

Eukaryotic cells execute complex transcriptional programs in which specific loci throughout the genome are regulated in distinct ways by targeted regulatory assemblies. We have applied this principle to generate synthetic CRISPR-based transcriptional programs in yeast and human cells. By extending guide RNAs to include effector protein recruitment sites, we construct modular scaffold RNAs that encode both target locus and regulatory action. Sets of scaffold RNAs can be used to generate synthetic multigene transcriptional programs in which some genes are activated and others are repressed. We apply this approach to flexibly redirect flux through a complex branched metabolic pathway in yeast. Moreover, these programs can be executed by inducing expression of the dCas9 protein, which acts as a single master regulatory control point. CRISPR-associated RNA scaffolds provide a powerful way to construct synthetic gene expression programs for a wide range of applications, including rewiring cell fates or engineering metabolic pathways.
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http://dx.doi.org/10.1016/j.cell.2014.11.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297522PMC
January 2015

Genome-Scale CRISPR-Mediated Control of Gene Repression and Activation.

Cell 2014 Oct 9;159(3):647-61. Epub 2014 Oct 9.

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA; California Institute for Quantitative Biomedical Research, San Francisco, CA 94158, USA; Center for RNA Systems Biology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address:

While the catalog of mammalian transcripts and their expression levels in different cell types and disease states is rapidly expanding, our understanding of transcript function lags behind. We present a robust technology enabling systematic investigation of the cellular consequences of repressing or inducing individual transcripts. We identify rules for specific targeting of transcriptional repressors (CRISPRi), typically achieving 90%-99% knockdown with minimal off-target effects, and activators (CRISPRa) to endogenous genes via endonuclease-deficient Cas9. Together they enable modulation of gene expression over a ∼1,000-fold range. Using these rules, we construct genome-scale CRISPRi and CRISPRa libraries, each of which we validate with two pooled screens. Growth-based screens identify essential genes, tumor suppressors, and regulators of differentiation. Screens for sensitivity to a cholera-diphtheria toxin provide broad insights into the mechanisms of pathogen entry, retrotranslocation and toxicity. Our results establish CRISPRi and CRISPRa as powerful tools that provide rich and complementary information for mapping complex pathways.
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http://dx.doi.org/10.1016/j.cell.2014.09.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253859PMC
October 2014

CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes.

Cell 2013 Jul 11;154(2):442-51. Epub 2013 Jul 11.

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.

The genetic interrogation and reprogramming of cells requires methods for robust and precise targeting of genes for expression or repression. The CRISPR-associated catalytically inactive dCas9 protein offers a general platform for RNA-guided DNA targeting. Here, we show that fusion of dCas9 to effector domains with distinct regulatory functions enables stable and efficient transcriptional repression or activation in human and yeast cells, with the site of delivery determined solely by a coexpressed short guide (sg)RNA. Coupling of dCas9 to a transcriptional repressor domain can robustly silence expression of multiple endogenous genes. RNA-seq analysis indicates that CRISPR interference (CRISPRi)-mediated transcriptional repression is highly specific. Our results establish that the CRISPR system can be used as a modular and flexible DNA-binding platform for the recruitment of proteins to a target DNA sequence, revealing the potential of CRISPRi as a general tool for the precise regulation of gene expression in eukaryotic cells.
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http://dx.doi.org/10.1016/j.cell.2013.06.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3770145PMC
July 2013