Publications by authors named "Neal G Ravindra"

17 Publications

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Single-cell longitudinal analysis of SARS-CoV-2 infection in human airway epithelium identifies target cells, alterations in gene expression, and cell state changes.

PLoS Biol 2021 03 17;19(3):e3001143. Epub 2021 Mar 17.

Department of Laboratory Medicine, Yale University, New Haven, Connecticut, United States of America.

There are currently limited Food and Drug Administration (FDA)-approved drugs and vaccines for the treatment or prevention of Coronavirus Disease 2019 (COVID-19). Enhanced understanding of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and pathogenesis is critical for the development of therapeutics. To provide insight into viral replication, cell tropism, and host-viral interactions of SARS-CoV-2, we performed single-cell (sc) RNA sequencing (RNA-seq) of experimentally infected human bronchial epithelial cells (HBECs) in air-liquid interface (ALI) cultures over a time course. This revealed novel polyadenylated viral transcripts and highlighted ciliated cells as a major target at the onset of infection, which we confirmed by electron and immunofluorescence microscopy. Over the course of infection, the cell tropism of SARS-CoV-2 expands to other epithelial cell types including basal and club cells. Infection induces cell-intrinsic expression of type I and type III interferons (IFNs) and interleukin (IL)-6 but not IL-1. This results in expression of interferon-stimulated genes (ISGs) in both infected and bystander cells. This provides a detailed characterization of genes, cell types, and cell state changes associated with SARS-CoV-2 infection in the human airway.
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http://dx.doi.org/10.1371/journal.pbio.3001143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007021PMC
March 2021

Neuroinvasion of SARS-CoV-2 in human and mouse brain.

J Exp Med 2021 03;218(3)

Department of Immunobiology, Yale School of Medicine, New Haven, CT.

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus on the consequences of CNS infections. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo. Finally, in autopsies from patients who died of COVID-19, we detect SARS-CoV-2 in cortical neurons and note pathological features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2.
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http://dx.doi.org/10.1084/jem.20202135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808299PMC
March 2021

Post-infectious inflammatory disease in MIS-C features elevated cytotoxicity signatures and autoreactivity that correlates with severity.

medRxiv 2020 Dec 4. Epub 2020 Dec 4.

Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening post-infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV2 infection in otherwise healthy children. Here, we define immune abnormalities in MIS-C compared to adult COVID-19 and pediatric/adult healthy controls using single-cell RNA sequencing, antigen receptor repertoire analysis, unbiased serum proteomics, and in vitro assays. Despite no evidence of active infection, we uncover elevated S100A-family alarmins in myeloid cells and marked enrichment of serum proteins that map to myeloid cells and pathways including cytokines, complement/coagulation, and fluid shear stress in MIS-C patients. Moreover, NK and CD8 T cell cytotoxicity genes are elevated, and plasmablasts harboring IgG1 and IgG3 are expanded. Consistently, we detect elevated binding of serum IgG from severe MIS-C patients to activated human cardiac microvascular endothelial cells in culture. Thus, we define immunopathology features of MIS-C with implications for predicting and managing this SARS-CoV2-induced critical illness in children.
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http://dx.doi.org/10.1101/2020.12.01.20241364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724682PMC
December 2020

Clinical implications of differences between real world and clinical trial usage of left ventricular assist devices for end stage heart failure.

PLoS One 2020 3;15(12):e0242928. Epub 2020 Dec 3.

Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, United States of America.

Importance: Patient outcomes in heart failure clinical trials are generally better than those observed in real-world settings. This may be related to stricter inclusion and exclusion criteria in clinical trials.

Objective: We study sought to characterize the clinical implications of differences between patients in clinical trials and those in a real-world registry of patients receiving left ventricular assist devices (LVADs).

Design, Setting, And Participants: This retrospective cohort study included all patients in INTERMACS (the Interagency Registry for Mechanically Assisted Circulatory Support) who were implanted with an axial flow LVAD from 2010 to 2015 to allow for equivalent comparisons.

Main Outcomes And Measures: Differences in patient characteristics and 2-year rates of adverse outcomes with those reported in the ENDURANCE and MOMENTUM 3 clinical trials. Survival analyses were used to assess the relationships between prespecified patient factors and clinical outcomes.

Results: Of the 10,937 LVAD recipients identified in INTERMACS between 2010-2015, 44% met at least 1 clinical trial exclusion criterion. The 2-year incidence of stroke and death amongst LVAD recipients in INTERMACS and the landmark clinical trials differed significantly (P<0.04, both). Nevertheless, patients who would have been excluded from the clinical trials did not have dramatically different 2-year mortality outcomes in INTERMACS [2y survival estimate: 66.4%, 95% CI (64.9-67.9%) versus 71.9%, 95% CI (70.6-73.1%)]. Clinical interventions driving a significantly increased risk of death were relatively rare (<5% of implants) and included mechanical ventilation, ECMO, severe thrombocytopenia, and dialysis.

Conclusions And Relevance: Most exclusion criteria used in LVAD clinical trials did not afford a substantially greater risk to patients in the real-world setting. In the relatively infrequent cases of end stage renal disease, thrombocytopenia, respiratory failure, and need for ECMO, the risks and benefits of LVAD therapy need careful weighting and further study.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242928PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714148PMC
January 2021

Genome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 Infection.

Cell 2021 01 20;184(1):76-91.e13. Epub 2020 Oct 20.

Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA; Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520, USA. Electronic address:

Identification of host genes essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may reveal novel therapeutic targets and inform our understanding of coronavirus disease 2019 (COVID-19) pathogenesis. Here we performed genome-wide CRISPR screens in Vero-E6 cells with SARS-CoV-2, Middle East respiratory syndrome CoV (MERS-CoV), bat CoV HKU5 expressing the SARS-CoV-1 spike, and vesicular stomatitis virus (VSV) expressing the SARS-CoV-2 spike. We identified known SARS-CoV-2 host factors, including the receptor ACE2 and protease Cathepsin L. We additionally discovered pro-viral genes and pathways, including HMGB1 and the SWI/SNF chromatin remodeling complex, that are SARS lineage and pan-coronavirus specific, respectively. We show that HMGB1 regulates ACE2 expression and is critical for entry of SARS-CoV-2, SARS-CoV-1, and NL63. We also show that small-molecule antagonists of identified gene products inhibited SARS-CoV-2 infection in monkey and human cells, demonstrating the conserved role of these genetic hits across species. This identifies potential therapeutic targets for SARS-CoV-2 and reveals SARS lineage-specific and pan-CoV host factors that regulate susceptibility to highly pathogenic CoVs.
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http://dx.doi.org/10.1016/j.cell.2020.10.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574718PMC
January 2021

Development and Validation of the Quick COVID-19 Severity Index: A Prognostic Tool for Early Clinical Decompensation.

Ann Emerg Med 2020 10 21;76(4):442-453. Epub 2020 Jul 21.

Department of Emergency Medicine, Yale University School of Medicine, New Haven, CT; Center for Medical Informatics, Yale University School of Medicine, New Haven, CT. Electronic address:

Study Objective: The goal of this study is to create a predictive, interpretable model of early hospital respiratory failure among emergency department (ED) patients admitted with coronavirus disease 2019 (COVID-19).

Methods: This was an observational, retrospective, cohort study from a 9-ED health system of admitted adult patients with severe acute respiratory syndrome coronavirus 2 (COVID-19) and an oxygen requirement less than or equal to 6 L/min. We sought to predict respiratory failure within 24 hours of admission as defined by oxygen requirement of greater than 10 L/min by low-flow device, high-flow device, noninvasive or invasive ventilation, or death. Predictive models were compared with the Elixhauser Comorbidity Index, quick Sequential [Sepsis-related] Organ Failure Assessment, and the CURB-65 pneumonia severity score.

Results: During the study period, from March 1 to April 27, 2020, 1,792 patients were admitted with COVID-19, 620 (35%) of whom had respiratory failure in the ED. Of the remaining 1,172 admitted patients, 144 (12.3%) met the composite endpoint within the first 24 hours of hospitalization. On the independent test cohort, both a novel bedside scoring system, the quick COVID-19 Severity Index (area under receiver operating characteristic curve mean 0.81 [95% confidence interval {CI} 0.73 to 0.89]), and a machine-learning model, the COVID-19 Severity Index (mean 0.76 [95% CI 0.65 to 0.86]), outperformed the Elixhauser mortality index (mean 0.61 [95% CI 0.51 to 0.70]), CURB-65 (0.50 [95% CI 0.40 to 0.60]), and quick Sequential [Sepsis-related] Organ Failure Assessment (0.59 [95% CI 0.50 to 0.68]). A low quick COVID-19 Severity Index score was associated with a less than 5% risk of respiratory decompensation in the validation cohort.

Conclusion: A significant proportion of admitted COVID-19 patients progress to respiratory failure within 24 hours of admission. These events are accurately predicted with bedside respiratory examination findings within a simple scoring system.
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http://dx.doi.org/10.1016/j.annemergmed.2020.07.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373004PMC
October 2020

COVID-19 infections and outcomes in a live registry of heart failure patients across an integrated health care system.

PLoS One 2020 30;15(9):e0238829. Epub 2020 Sep 30.

Department of Internal Medicine, Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, CT, United States of America.

Background: Patients with comorbid conditions have a higher risk of mortality with SARS-CoV-2 (COVID-19) infection, but the impact on heart failure patients living near a disease hotspot is unknown. Therefore, we sought to characterize the prevalence and outcomes of COVID-19 in a live registry of heart failure patients across an integrated health care system in Connecticut.

Methods: In this retrospective analysis, the Yale Heart Failure Registry (NCT04237701) that includes 26,703 patients with heart failure across a 6-hospital integrated health care system in Connecticut was queried on April 16th, 2020 for all patients tested for COVID-19. Sociodemographic and geospatial data as well as, clinical management, respiratory failure, and patient mortality were obtained via the real-time registry. Data on COVID-19 specific care was extracted by retrospective chart review.

Results: COVID-19 testing was performed on 900 symptomatic patients, comprising 3.4% of the Yale Heart Failure Registry (N = 26,703). Overall, 206 (23%) were COVID- 19+. As compared to COVID-19-, these patients were more likely to be older, black, have hypertension, coronary artery disease, and were less likely to be on renin angiotensin blockers (P<0.05, all). COVID-19- patients tended to be more diffusely spread across the state whereas COVID-19+ were largely clustered around urban centers. 20% of COVID-19+ patients died, and age was associated with increased risk of death [OR 1.92 95% CI (1.33-2.78); P<0.001]. Among COVID-19+ patients who were ≥85 years of age rates of hospitalization were 87%, rates of death 36%, and continuing hospitalization 62% at time of manuscript preparation.

Conclusions: In this real-world snapshot of COVID-19 infection among a large cohort of heart failure patients, we found that a small proportion had undergone testing. Patients found to be COVID-19+ tended to be black with multiple comorbidities and clustered around lower socioeconomic status communities. Elderly COVID-19+ patients were very likely to be admitted to the hospital and experience high rates of mortality.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238829PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526909PMC
October 2020

Neuroinvasion of SARS-CoV-2 in human and mouse brain.

bioRxiv 2020 Sep 8. Epub 2020 Sep 8.

Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA.

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus whether the virus can infect the brain, or what the consequences of CNS infection are. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in the infected and neighboring neurons. However, no evidence for the type I interferon responses was detected. We demonstrate that neuronal infection can be prevented either by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate that SARS-CoV-2 neuroinvasion, but not respiratory infection, is associated with mortality. Finally, in brain autopsy from patients who died of COVID-19, we detect SARS-CoV-2 in the cortical neurons, and note pathologic features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV2, and an unexpected consequence of direct infection of neurons by SARS-CoV-2.
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http://dx.doi.org/10.1101/2020.06.25.169946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491522PMC
September 2020

Patient factors associated with SARS-CoV-2 in an admitted emergency department population.

J Am Coll Emerg Physicians Open 2020 May 22. Epub 2020 May 22.

Department of Emergency Medicine Yale University School of Medicine New Haven CT.

: The SARS-CoV-2 (COVID-19) virus has wide community spread. The aim of this study was to describe patient characteristics and to identify factors associated with COVID-19 among emergency department patients under investigation for COVID-19 who were admitted to the hospital. : This was a retrospective observational study from eight emergency departments within a nine-hospital health system. Patients with COVID-19 testing around the time of hospital admission were included. The primary outcome measure was COVID-19 test result. Patient characteristics were described and a multivariable logistic regression model was used to identify factors associated with a positive COVID-19 test. : During the study period from March 1, 2020 to April 8, 2020, 2,182 admitted patients had a test resulted for COVID-19. Of these patients, 786 (36%) had a positive test result. For COVID positive patients, 63 (8.1%) died during hospitalization. COVID-19 positive patients had lower pulse oximetry (0.91 [95%CI], [0.88-0.94]), higher temperatures (1.36 [1.26-1.47]), and lower leukocyte counts than negative patients (0.78 [0.75-0.82]). Chronic lung disease (OR 0.68, [0.52-0.90]) and histories of alcohol (0.64 [0.42-0.99]) or substance abuse (0.39 [0.25-0.62]) were less likely to be associated with a positive COVID-19 result. : We observed a high percentage of positive results among an admitted emergency department cohort under investigation for COVID-19. Patient factors may be useful in early differentiation of patients with COVID-19 from similarly presenting respiratory illnesses although no single factor will serve this purpose. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/emp2.12145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280703PMC
May 2020

Clinical impact of concomitant tricuspid valve procedures during left ventricular assist device implantation.

J Heart Lung Transplant 2020 09 19;39(9):926-933. Epub 2020 May 19.

Center for Outcomes Research & Evaluation (CORE), Yale School of Medicine and Yale New Haven Health, New Haven, Connecticut; Section of Cardiovascular Medicine, Yale School of Medicine and Yale New Haven Health, New Haven, Connecticut. Electronic address:

Background: Tricuspid regurgitation (TR) is common in patients with end-stage heart failure receiving left ventricular assist devices (LVADs), but the benefit of concomitant tricuspid valve procedures (TVPs) remains uncertain. This study examined the impact of TVP at the time of LVAD implantation on clinical outcomes and quality of life (QOL) metrics.

Methods: We included adult patients in the Interagency Registry for Mechanical Circulatory Support database with various degrees of TR who received continuous-flow LVADs from 2008 to 2017. Patients undergoing concomitant TVP were compared with those without the intervention in a stratified analysis. Descriptive analyses, survival analyses, and Andersen‒Gill hazard models were used as appropriate to examine associations with clinical and patient-centered QOL outcomes.

Results: Our analysis included 8,263 (53.1%) mild, 4,252 (33.3%) moderate, and 2,100 (13.5%) severe TR cases. TVP rate increased with severity: 8.6% of mild, 18.0% of moderate, and 43.9% of severe cases. TVP was not associated with survival benefit in cases of mild (adjusted hazard ratio [aHR]: 0.97, 95% CI: 0.79-1.19, p = 0.75), moderate (aHR: 1.03, 95% CI: 0.88-1.20, p = 0.72), or severe (aHR: 1.20, 95% CI: 0.98-1.48, p = 0.08) TR. For patients with combined moderate or severe TR, TVP was associated with increased mortality (log-rank p < 0.01, aHR: 1.13, 95% CI: 1.00-1.27, p = 0.04). After adjusting for TR severity, TVP was associated with increased risk of bleeding, arrhythmia, and stroke (p < 0.01 each) and no improvements in QOL (p > 0.05).

Conclusions: TVP at the time of LVAD implantation was not associated with either improved survival or QOL, and there were associations with increased risk of adverse events among patients with moderate and severe TR.
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http://dx.doi.org/10.1016/j.healun.2020.05.007DOI Listing
September 2020

Psychiatric Comorbidity and Outcomes After Left Ventricular Assist Device Implantation for End-Stage Heart Failure.

JACC Heart Fail 2020 07 10;8(7):569-577. Epub 2020 Jun 10.

Division of Cardiac Surgery, Yale School of Medicine and Yale New Haven Health, New Haven, Connecticut; Center for Outcomes Research & Evaluation, Yale School of Medicine and Yale New Haven Health, New Haven, Connecticut. Electronic address:

Background: Psychiatric comorbidities play a key role in patient selection for left ventricular assist devices (LVADs), but their impact on clinical outcomes is unknown.

Objectives: The goal of this study was to examine the clinical impact of psychiatric illness on outcomes in patients receiving LVADs for end-stage heart failure (HF).

Methods: The study identified adults in the Interagency Registry for Mechanically Assisted Circulatory Support with psychiatric comorbidities (history of alcohol abuse, drug use, narcotic dependence, depression, and other major psychiatric diagnoses) receiving continuous-flow LVADs from 2008 to 2017. Demographic characteristics, survival, adverse events, and quality of life scores were compared for patients with and without each psychiatric comorbidity.

Results: Over the study period, the prevalence of psychiatric comorbidities was low: alcohol abuse, n = 1,093 (5.5%); drug use, n = 1,077 (5.4%); narcotic dependence, n = 96 (0.5%); depression, n = 401 (2.0%); and other major psychiatric illnesses, n = 265 (1.4%). Narcotic dependence (adjusted hazard ratio: 1.9; 95% confidence interval: 1.2 to 3.0; p = 0.004) and other major psychiatric illnesses (adjusted hazard ratio: 1.4; 95% confidence interval: 1.0 to 1.9; p = 0.02) were associated with increased risk of mortality, whereas alcohol abuse, drug use, and depression were not. All comorbidities except narcotic dependence were associated with increased risk of rehospitalization and device-related infection (both p < 0.05). Kansas City Cardiomyopathy Questionnaire scores were lower from 6 to 24 months' post-implantation among patients with psychiatric comorbidities (p < 0.05).

Conclusions: Despite a low prevalence of psychiatric comorbidities among LVAD recipients, these conditions were associated with mortality risk, adverse events, and poorer quality of life. Further study is needed to understand how specific psychiatric conditions affect outcomes and how to best manage this vulnerable patient population.
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http://dx.doi.org/10.1016/j.jchf.2020.03.011DOI Listing
July 2020

Single-cell longitudinal analysis of SARS-CoV-2 infection in human bronchial epithelial cells.

bioRxiv 2020 May 7. Epub 2020 May 7.

Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA.

SARS-CoV-2, the causative agent of COVID-19, has resulted in more than 3,000,000 infections and 200,000 deaths. There are currently no approved drugs or vaccines for the treatment or prevention of COVID-19. Enhanced understanding of SARS-CoV-2 infection and pathogenesis is critical for the development of therapeutics. To reveal insight into viral replication, cell tropism, and host-viral interactions of SARS-CoV-2 we performed single-cell RNA sequencing of experimentally infected human bronchial epithelial cells (HBECs) in air-liquid interface cultures over a time-course. This revealed novel polyadenylated viral transcripts and highlighted ciliated cells as the major target of infection, which we confirmed by electron microscopy. Over the course of infection, cell tropism of SARS-CoV-2 expands to other epithelial cell types including basal and club cells. Infection induces cell intrinsic expression of type I and type III IFNs and IL6 but not IL1. This results in expression of interferon stimulated genes in both infected and bystander cells. Here, we have conducted an in-depth analysis of SARS-CoV-2 infection in HBECs and provide a detailed characterization of genes, cell types, and cell state changes associated with the infection.
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http://dx.doi.org/10.1101/2020.05.06.081695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263511PMC
May 2020

Clinical Outcomes After Left Ventricular Assist Device Implantation in Older Adults: An INTERMACS Analysis.

JACC Heart Fail 2019 12;7(12):1069-1078

Division of Cardiology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York. Electronic address:

Objectives: The purpose of this study was to examine outcomes after left ventricular assist device (LVAD) implantation in older adults (>75 years of age).

Background: An aging heart failure population together with improvements in mechanical circulatory support (MCS) technology have led to increasing LVAD implantations in older adults. However, data presenting age-specific outcomes are limited.

Methods: Adult patients in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) who required durable MCS between 2008 and 2017 were included. Patients were stratified by 4 age groups: <55 years of age, 55 to 64 years of age, and >75 years of age. Kaplan-Meier survival estimates were used to assess post-LVAD outcomes, with log-rank testing used to compare groups. Univariate and multivariate cox proportional hazard regression models were used to determine predictors of survival and complications.

Results: A total of 20,939 individuals received an LVAD during the study period: 7,743 (37.0%) were <55 years of age, 6,755 (32.3%) were 55 to 64 years of age, 5,418 (25.9%) were 65 to 74 years of age, and 1,023 (4.9%) were ≥75 years of age or older. After multivariate adjustment, adults ≥75 years of age had increased mortality post-LVAD implantation. Elderly patients with LVADs had a higher incidence of gastrointestinal bleeding but lower rates of device thrombosis. Compared to 84.5% of patients <55 years of age who were discharged home, only 46.8% of adults ≥75 years of age were discharged home following implantation (p < 0.001). Use of a RVAD, serum albumin level, and 6-min walk test distances were identified as predictors of outcomes in the oldest cohort.

Conclusions: Despite careful selection of older adults for LVAD implantation, age remains a significant predictor of mortality. Higher bleeding and lower clotting risk in elderly patients with LVADs support the use of a less intense antithrombotic regimen in this unique population.
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http://dx.doi.org/10.1016/j.jchf.2019.10.004DOI Listing
December 2019

Neurohormonal Blockade and Clinical Outcomes in Patients With Heart Failure Supported by Left Ventricular Assist Devices.

JAMA Cardiol 2020 02;5(2):175-182

Center for Outcomes Research & Evaluation, Yale University and Yale University School of Medicine, New Haven, Connecticut.

Importance: Left ventricular assist devices (LVADs) improve outcomes in patients with advanced heart failure, but little is known about the role of neurohormonal blockade (NHB) in treating these patients.

Objective: To analyze the association between NHB blockade and outcomes in patients with LVADs.

Design, Setting, And Participants: This retrospective cohort analysis of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) included patients from more than 170 centers across the United States and Canada with continuous flow LVADs from 2008 to 2016 who were alive with the device in place at 6 months after implant. The data were analyzed between February and November 2019.

Exposures: Patients were stratified based on exposure to NHB and represented all permutations of the following drug classes: angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, β-blockers, and mineralocorticoid antagonists.

Main Outcomes And Measures: The outcomes of interest were survival at 4 years and quality of life at 2 years based on Kansas City Cardiomyopathy Questionnaire scores and a 6-minute walk test.

Results: A total of 12 144 patients in INTERMACS met inclusion criteria, of whom 2526 (20.8% ) were women, 8088 (66.6%) were white, 3024 (24.9%) were African American, and 753 (6.2%) were Hispanic; the mean (SD) age was 56.8 (12.9) years. Of these, 10 419 (85.8%) were receiving NHB. Those receiving any NHB medication at 6 months had a better survival rate at 4 years compared with patients not receiving NHB (56.0%; 95% CI, 54.5%-57.5% vs 43.9%; 95% CI, 40.5%-47.7%). After sensitivity analyses with an adjusted model, this trend persisted with patients receiving triple therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, β-blocker, and mineralocorticoid antagonist having the lowest hazard of death compared with patients in the other groups (hazard ratio, 0.34; 95% CI, 0.28-0.41). Compared with patients not receiving NHB, use of NHB was associated with a higher Kansas City Cardiomyopathy Questionnaire score (66.6; bootstrapped 95% CI, 65.8-67.3 vs 63.0; bootstrapped 95% CI, 60.1-65.8; P = .02) and a 6-minute walk test (1103 ft; bootstrapped 95% CI, 1084-1123 ft vs 987 ft; bootstrapped 95% CI, 913-1060 ft; P < .001).

Conclusions And Relevance: Among patients with LVADs who tolerated NHB therapy, continued treatment was associated with improved survival and quality of life. The optimal heart failure regimen for patients after LVAD implant may be the initiation and continuation of guideline-directed medical therapy.
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http://dx.doi.org/10.1001/jamacardio.2019.4965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865330PMC
February 2020

Clinical Implications of Respiratory Failure in Patients Receiving Durable Left Ventricular Assist Devices for End-Stage Heart Failure.

Circ Heart Fail 2019 11 11;12(11):e006369. Epub 2019 Nov 11.

Section of Cardiovascular Medicine (P.E.M., S.R., N.R.D., T.A.), Yale University School of Medicine, New Haven, CT.

Background: The impact of respiratory failure on patients undergoing left ventricular assist device (LVAD) implantation is not well understood, especially since these patients were excluded from landmark clinical trials. We sought to evaluate the associations between immediate preimplant and postimplant respiratory failure on outcomes in advanced heart failure patients undergoing LVAD implantation.

Methods And Results: We included all patients in the Interagency Registry for Mechanically Assisted Circulatory Support who were implanted with continuous-flow LVADs from 2008 to 2016. Of the 16 362 patients who underwent continuous-flow LVAD placement, 906 (5.5%) required preimplant intubation within 48 hours before implantation, and 1001 (6.1%) patients developed respiratory failure within 1 week after implantation. A higher proportion of patients requiring preimplant intubation were Interagency Registry for Mechanically Assisted Circulatory Support profile 1, required mechanical circulatory support, and presented with cardiac arrest or myocardial infarction (<0.001, all). At 1 year, 54.3% of patients intubated preimplant were alive without transplant, 20.1% had been transplanted, and 24.2% died before transplant. Patients requiring preimplant intubation had higher rates of postimplant complications, including bleeding, stroke, and right ventricular assist device implantation (<0.01 for all). Among Interagency Registry for Mechanically Assisted Circulatory Support profile 1 patients, preimplant intubation incurred additional risk of death at 1 year compared with Interagency Registry for Mechanically Assisted Circulatory Support profile 1 patients not intubated (hazard ratio, 1.37 [95% CI, 1.13-1.65]; =0.001). After multivariable analysis, both preimplant intubation (hazard ratio, 1.20 [95% CI, 1.03-1.41]; =0.021) and respiratory failure within 1 week (hazard ratio, 2.54 [95% CI, 2.26-2.85]; <0.001) were associated with higher all-cause 1-year mortality.

Conclusions: Respiratory failure both before and after LVAD implantation identifies an advanced heart failure population with significantly worse 1-year mortality. This data might be helpful in counseling patients and their families about expectations about life with an LVAD.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006369DOI Listing
November 2019

Patient-centered and Patient-independent Technologies in Acute Neurological Injury and the Art of Making Useful Medical Contributions: 
An Interview with Kevin Sheth, MD.

Authors:
Neal G Ravindra

Yale J Biol Med 2018 09 21;91(3):345-351. Epub 2018 Sep 21.

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6153623PMC
September 2018

Molecular mechanisms of force production in clathrin-mediated endocytosis.

FEBS Lett 2018 11 28;592(21):3586-3605. Epub 2018 Jul 28.

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.

During clathrin-mediated endocytosis (CME), a flat patch of membrane is invaginated and pinched off to release a vesicle into the cytoplasm. In yeast CME, over 60 proteins-including a dynamic actin meshwork-self-assemble to deform the plasma membrane. Several models have been proposed for how actin and other molecules produce the forces necessary to overcome the mechanical barriers of membrane tension and turgor pressure, but the precise mechanisms and a full picture of their interplay are still not clear. In this review, we discuss the evidence for these force production models from a quantitative perspective and propose future directions for experimental and theoretical work that could clarify their various contributions.
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http://dx.doi.org/10.1002/1873-3468.13192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231980PMC
November 2018