Publications by authors named "Frank Sellke"

396 Publications

Outcomes of diabetic patients with end-stage heart failure listed for heart transplantation: A propensity-matched analysis.

Clin Transplant 2022 Jan 12:e14590. Epub 2022 Jan 12.

Division of Heart Failure and Transplant, University of Iowa Hospitals and Clinics, Iowa, Iowa, USA.

Background: We investigated the current trends and outcomes of diabetic patients listed for heart transplants in the U.S. and provided a method for risk-stratification.

Methods: Using data from the United Network for Organ Sharing (UNOS), we identified heart failure patients listed for heart transplants between 2010 and 2019. Diabetic patients were propensity-matched with non-diabetics, and waitlist mortality as well as post-transplant graft survival were compared between the two groups. Further risk-stratification of diabetic patients was done based on the risk factors that independently predict graft failure.

Results: 28,928 adult patients (30% diabetic) with end-stage heart failure were added to the waitlist over the study period. In the propensity-matched cohort, waitlist mortality was higher in diabetic patients compared to non-diabetics (HR = 1.13 (95% CI = 1.04-1.22, P = .002). Over the study period, 5739 patients with diabetes were transplanted. In the propensity-matched cohorts of transplant recipients, the rate of graft failure was significantly higher for diabetic patients (23.3%) compared to non-diabetics (20.4%); HR = 1.17, 95% CI = 1.08-1.26, P < .001. We identified 12 risk factors of graft failure among diabetic patients and developed a risk score that further risk-stratify these patients. Diabetic patients at low risk (score≤4) had similar graft survival as patients without diabetes (HR = .91, 95% CI = .82-1.01, P = .06). On the other hand, high-risk diabetic patients had worse graft survival compared to non-diabetics (HR = 1.52, 95% CI = 1.38-1.67, P < .001).

Conclusion: Among patients with end-stage heart failure, pre-existing diabetes was associated with higher waitlist mortality and worse graft survival. However, with careful patient selection, graft survival is similar to those without diabetes.
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http://dx.doi.org/10.1111/ctr.14590DOI Listing
January 2022

2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

J Am Coll Cardiol 2022 Jan 9;79(2):197-215. Epub 2021 Dec 9.

Aim: The executive summary of the American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions coronary artery revascularization guideline provides the top 10 items readers should know about the guideline. In the full guideline, the recommendations replace the 2011 coronary artery bypass graft surgery guideline and the 2011 and 2015 percutaneous coronary intervention guidelines. This summary offers a patient-centric approach to guide clinicians in the treatment of patients with significant coronary artery disease undergoing coronary revascularization, as well as the supporting documentation to encourage their use.

Methods: A comprehensive literature search was conducted from May 2019 to September 2019, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Collaboration, CINHL Complete, and other relevant databases. Additional relevant studies, published through May 2021, were also considered.

Structure: Recommendations from the earlier percutaneous coronary intervention and coronary artery bypass graft surgery guidelines have been updated with new evidence to guide clinicians in caring for patients undergoing coronary revascularization. This summary includes recommendations, tables, and figures from the full guideline that relate to the top 10 take-home messages. The reader is referred to the full guideline for graphical flow charts, supportive text, and tables with additional details about the rationale for and implementation of each recommendation, and the evidence tables detailing the data considered in the development of this guideline.
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http://dx.doi.org/10.1016/j.jacc.2021.09.005DOI Listing
January 2022

2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

J Am Coll Cardiol 2022 Jan 9;79(2):e21-e129. Epub 2021 Dec 9.

Aim: The guideline for coronary artery revascularization replaces the 2011 coronary artery bypass graft surgery and the 2011 and 2015 percutaneous coronary intervention guidelines, providing a patient-centric approach to guide clinicians in the treatment of patients with significant coronary artery disease undergoing coronary revascularization as well as the supporting documentation to encourage their use.

Methods: A comprehensive literature search was conducted from May 2019 to September 2019, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Collaboration, CINHL Complete, and other relevant databases. Additional relevant studies, published through May 2021, were also considered.

Structure: Coronary artery disease remains a leading cause of morbidity and mortality globally. Coronary revascularization is an important therapeutic option when managing patients with coronary artery disease. The 2021 coronary artery revascularization guideline provides recommendations based on contemporary evidence for the treatment of these patients. The recommendations present an evidence-based approach to managing patients with coronary artery disease who are being considered for coronary revascularization, with the intent to improve quality of care and align with patients' interests.
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http://dx.doi.org/10.1016/j.jacc.2021.09.006DOI Listing
January 2022

2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

Circulation 2022 Jan 9;145(3):e4-e17. Epub 2021 Dec 9.

ACC/AHA Representative.

Aim: The executive summary of the American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions coronary artery revascularization guideline provides the top 10 items readers should know about the guideline. In the full guideline, the recommendations replace the 2011 coronary artery bypass graft surgery guideline and the 2011 and 2015 percutaneous coronary intervention guidelines. This summary offers a patient-centric approach to guide clinicians in the treatment of patients with significant coronary artery disease undergoing coronary revascularization, as well as the supporting documentation to encourage their use.

Methods: A comprehensive literature search was conducted from May 2019 to September 2019, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Collaboration, CINHL Complete, and other relevant databases. Additional relevant studies, published through May 2021, were also considered. Structure: Recommendations from the earlier percutaneous coronary intervention and coronary artery bypass graft surgery guidelines have been updated with new evidence to guide clinicians in caring for patients undergoing coronary revascularization. This summary includes recommendations, tables, and figures from the full guideline that relate to the top 10 take-home messages. The reader is referred to the full guideline for graphical flow charts, supportive text, and tables with additional details about the rationale for and implementation of each recommendation, and the evidence tables detailing the data considered in the development of this guideline.
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http://dx.doi.org/10.1161/CIR.0000000000001039DOI Listing
January 2022

COVID-19 Vaccine Boosters: The Good, the Bad, and the Ugly.

Vaccines (Basel) 2021 Nov 9;9(11). Epub 2021 Nov 9.

Universal Scientific Education and Research Network (USERN), https://usern.tums.ac.ir, Tehran 1417614411, Iran.

Pursuing vaccinations against COVID-19 brings hope to limit the spread of SARS-CoV-2 and remains the most rational decision under pandemic conditions. However, it does not come without challenges, including temporary shortages in vaccine doses, significant vaccine inequity, and questions regarding the durability of vaccine-induced immunity that remain unanswered. Moreover, SARS-CoV-2 has undergone evolution with the emergence of its novel variants, characterized by enhanced transmissibility and ability to at least partially evade neutralizing antibodies. At the same time, serum antibody levels start to wane within a few months after vaccination, ultimately increasing the risk of breakthrough infections. This article discusses whether the administration of booster doses of COVID-19 vaccines is urgently needed to control the pandemic. We conclude that, at present, optimizing the immunity level of wealthy populations cannot come at the expense of low-income regions that suffer from vaccine unavailability. Although the efficiency of vaccination in protecting from infection may decrease over time, current data show that efficacy against severe disease, hospitalization, and death remains at a high level. If vaccine coverage continues at extremely low levels in various regions, including African countries, SARS-CoV-2 may sooner or later evolve into variants better adapted to evade natural and vaccine-induced immunity, ultimately bringing a global threat that, of course, includes wealthy populations. We offer key recommendations to increase vaccination rates in low-income countries. The pandemic is, by definition, a major epidemiological event and requires looking beyond one's immediate self-interest; otherwise, efforts to contain it will be futile.
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http://dx.doi.org/10.3390/vaccines9111299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8623745PMC
November 2021

The Challenge of Estimating Treatment Effects in Cardiac Surgery.

JAMA Cardiol 2021 12;6(12):1355-1356

Warren Alpert Medical School, Brown University, and Division of Cardiothoracic Surgery, Rhode Island Hospital, Providence.

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http://dx.doi.org/10.1001/jamacardio.2021.4833DOI Listing
December 2021

The impact of the American Association for Thoracic Surgery on National Institutes of Health grant funding for cardiothoracic surgeons.

J Thorac Cardiovasc Surg 2021 Oct 28. Epub 2021 Oct 28.

Department of Cardiothoracic Surgery, Stanford University, Stanford, Calif. Electronic address:

Objectives: The American Association for Thoracic Surgery, through its annual meeting, pilot grant funding, Scientific Affairs and Government Relations Committee activity, and academic development programs (Grant Writing Workshop, Clinical Trials Course, Innovation Summit), has aimed to develop the research careers of cardiothoracic surgeons. We hypothesized that American Association for Thoracic Surgery activities have helped increase National Institutes of Health grants awarded to cardiothoracic surgeons.

Methods: A database of 1869 academic cardiothoracic surgeons in the United States was created in December 2020. National Institutes of Health grant records from 1985 to 2020 were obtained for each surgeon using National Institutes of Health Research Portfolio Online Reporting Tools Expenditures and Results. Analyses were normalized to the number of active surgeons per year, based on the year of each surgeon's earliest research publication on Scopus.

Results: A total of 346 cardiothoracic surgeons have received 696 National Institutes of Health grants totaling more than $1.5 billion in funding, with 48 surgeons actively serving as principal investigator of 66 R01 grants in 2020. The prevalence of research grants (7.4 vs 5.6 grants per 100 active surgeons, P < .0001), percentage of surgeons with a research grant (5.3% vs 4.7%, P = .0342), and number of research grants per funded surgeon (1.4 vs 1.2 grants, P < .0001) were significantly greater during the Scientific Affairs and Government Relations era (2003-2020) than the pre-Scientific Affairs and Government Relations era (1985-2002). The incidence of new research grants after surgeon participation in an American Association for Thoracic Surgery academic development program was significantly greater than that in the absence of participation (3.5 vs 1.1 new grants per 100 surgeons per year, P < .0001).

Conclusions: Through dedicated efforts and programs, the American Association for Thoracic Surgery has provided effective support to help increase National Institutes of Health grant funding awarded to cardiothoracic surgeons.
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http://dx.doi.org/10.1016/j.jtcvs.2021.10.031DOI Listing
October 2021

Methylome of skeletal muscle tissue in patients with hypertension and diabetes undergoing cardiopulmonary bypass.

Epigenomics 2021 12 22;13(23):1853-1866. Epub 2021 Nov 22.

Alpert Medical School of Brown University, Department of Surgery, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA.

Epigenomic changes occurring during surgery have been neglected in research; diabetes and hypertension can affect the epigenome but little is known about the epigenetics of skeletal muscle (SKM). DNA methylation was profiled via Illumina MethylationEPIC arrays in SKM samples obtained at the beginning and end of heart surgery with cardiopulmonary bypass. Methylation in patients with hypertension and diabetes was significantly different, more so for uncontrolled diabetes; hypertension alone produced minimal effect. The affected pathways involved IL-1, IL-12, IL-18, TNF-α, IFN-γ, VEGF, NF-κB and Wnt signaling, apoptosis and DNA damage response. Significant changes occurred during surgery and included loci in the Hippo-YAP/TAZ pathway. Cardiopulmonary bypass surgery affects the SKM methylome, and the combination of hypertension and diabetes induces changes in the SKM epigenome in contrast to hypertension alone.
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http://dx.doi.org/10.2217/epi-2021-0388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619827PMC
December 2021

Extracellular vesicles improve diastolic function and substructure in normal and high-fat diet models of chronic myocardial ischemia.

J Thorac Cardiovasc Surg 2021 Oct 13. Epub 2021 Oct 13.

Cardiovascular Research Center, Rhode Island Hospital, Providence, RI; Division of Cardiothoracic Surgery, Alpert Medical School of Brown University and Rhode Island Hospital, Providence, RI. Electronic address:

Objective: The burden of mortality and morbidity of cardiovascular disease is in part due to substantial fibrosis accelerated by coexisting risk factors. This study aims to evaluate the effect of extracellular vesicle therapy on diastolic function and myocardial fibrosis in the setting of chronic myocardial ischemia with and without a high-fat diet.

Methods: Forty male Yorkshire swine were administered a normal or high-fat diet. At 11 weeks of age, they underwent placement of an ameroid constrictor on their left circumflex coronary artery. Both dietary groups then received either intramyocardial injection of vehicle saline as controls or extracellular vesicles as treatment into the ischemic territory (normal diet control, n = 8; high-fat diet controls, n = 11) or extracellular vesicles (normal diet extracellular vesicles, n = 9; high-fat diet extracellular vesicles, n = 12). Five weeks later, hemodynamic parameters, histology, and selected protein expression were evaluated.

Results: Extracellular vesicles reduced end-diastolic pressure volume relationship (P = .002), perivascular collagen density (P = .031), calcium mineralization (P = .026), and cardiomyocyte diameter (P < .0001), and upregulated osteopontin (P = .0046) and mechanistic target of rapamycin (P = .021). An interaction between extracellular vesicles and diet was observed in the vimentin area (P = .044) and fraction of myofibroblast markers to total vimentin (P = .049). Significant changes across diet were found with reductions in muscle fiber area (P = .026), tumor necrosis factor α (P = .0002), NADPH oxidase 2 and 4 (P = .0036, P = .008), superoxide dismutase 1 (P = .034), and phosphorylated glycogen synthase kinase 3β (P = .020).

Conclusions: Extracellular vesicle therapy improved the myocardium's ability to relax and is likely due to structural improvements at the extracellular matrix and cellular levels.
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http://dx.doi.org/10.1016/j.jtcvs.2021.07.062DOI Listing
October 2021

Rationale and design of the safe and timely antithrombotic removal - ticagrelor (STAR-T) trial: A prospective, multi-center, double-blind, randomized controlled trial evaluating reductions in postoperative bleeding with intraoperative removal of ticagrelor by the drugsorb™-ATR device in patients undergoing cardiothoracic surgery within 48 hours from last ticagrelor dose.

Am Heart J 2021 Nov 1;245:19-28. Epub 2021 Nov 1.

CytoSorbents Inc, Princeton, NJ.

Background: Ticagrelor is often administered to patients with acute coronary syndromes. However, when these patients require urgent or emergent cardiothoracic (CT) surgery the presence of ticagrelor significantly increases surgical bleeding. The goal of the current trial is to evaluate the effectiveness and safety of the DrugSorb-ATR hemoadsorption device for the intraoperative removal of ticagrelor to reduce postoperative bleeding in the above patient population. The Safe and Timely Antithrombotic Removal - Ticagrelor (STAR-T) Trial is a multi-center, double-blind, randomized, controlled trial enrolling patients who require cardiothoracic surgery on cardiopulmonary bypass (CPB) within 48 hours of last ticagrelor dose.

Methods: Subjects will be randomized 1:1 to receive either the DrugSorb-ATR device or an identical sham device during CPB. The study will enroll up to 120 subjects at 20 U.S centers, and the primary outcome is the composite of fatal perioperative bleeding, moderate/severe/massive bleeding according to the Universal Definition of Perioperative Bleeding in Cardiac Surgery (UDPB), and 24 hours chest tube drainage. The components of the composite are hierarchically ranked according to clinical significance and the primary analysis will utilize the Win Ratio method. Percent change in ticagrelor levels before and after CPB (drug removal) will be the key secondary endpoint. An independent Clinical Events Committee will adjudicate all clinical endpoints including safety endpoints relating to postoperative thrombotic events. Subjects will be followed through 30 days after the index operation.

Conclusions: The results from STAR-T, if positive, will potentially support FDA market approval for DrugSorb-ATR, and provide a solution to an important unmet clinical need.
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http://dx.doi.org/10.1016/j.ahj.2021.10.188DOI Listing
November 2021

Glycemic control is not associated with neurocognitive decline after cardiac surgery.

J Card Surg 2022 Jan 28;37(1):138-147. Epub 2021 Oct 28.

Department of Surgery, Division of Cardiothoracic Surgery, Lifespan Hospitals, Warren Alpert School of Medicine of Brown University, Providence, Rhode Island, USA.

Background: Whether perioperative glycemic control is associated with neurocognitive decline (NCD) after cardiac surgery was examined.

Methods: Thirty patients undergoing cardiac surgery utilizing cardiopulmonary bypass (CPB) were screened for NCD preoperatively and on postoperative day 4 (POD4). Indices of glucose control were examined. Serum cytokine levels were measured and human transcriptome analysis was performed on blood samples. Neurocognitive data are presented as a change from baseline to POD4 in a score standardized with respect to age and gender.

Results: A decline in neurocognitive function was identified in 73% (22/30) of patients on POD4. There was no difference in neurocognitive function between patients with elevated HbA1c levels preoperatively (p = .973) or elevated fasting blood glucose levels the morning of surgery (>126 mg/dl, p = .910), or a higher maximum blood glucose levels during CPB (>180 mg/dl, p = .252), or higher average glucose levels during CPB (>160 mg/dl, p = .639). Patients with postoperative leukocytosis (WBC ≥ 10.5) had more NCD when compared to their baseline function (p = .03). Patients with elevated IL-8 levels at 6 h postoperatively had a significant decline in NCD at POD4 (p = .04). Human transcriptome analysis demonstrated unique and differential patterns of gene expression in patients depending on the presence of DM and NCD.

Conclusions: Perioperative glycemic control does not have an effect on NCD soon after cardiac surgery. The profile of gene expression was altered in patients with NCD with or without diabetes.
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http://dx.doi.org/10.1111/jocs.16102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8752128PMC
January 2022

Changing Demographics, Temporal Trends in Waitlist, and Posttransplant Outcomes After Heart Transplantation in the United States: Analysis of the UNOS Database 1991-2019.

Circ Heart Fail 2021 11 25;14(11):e008764. Epub 2021 Oct 25.

Division of Heart Failure and Transplant (A.B.), University of Iowa Hospitals and Clinics, Iowa City.

Background: We sought to investigate temporal trends in patient characteristics, waitlist, and posttransplant outcomes after heart transplantation in the United States.

Methods: Using data from the United Network of Organ Sharing, we identified adults listed for heart transplantation between 1991 and 2019. Patients were divided into 4 eras based on the 3 time points in which changes were made to the patient selection/allocation policy (Era 1=January 1991-January 1999; Era 2=January 1999-July 2006; Era 3=July 2006-October 2018; and Era 4=October 2018-March 2020), and patient characteristics, waitlist, and posttransplant outcomes were evaluated for each era.

Results: Between 1991 and 2019, 95 179 patients were added to the heart transplantation waitlist. Compared with Era 1, patients listed in Era 4 were older (mean age: 50 versus 52 years) and with higher risk comorbidities (eg, 10% versus 28.8% diabetes, 23.3% versus 35.6% obese). Over the study period, 22 738 patients died or were permanently delisted for deterioration on the waitlist while 61 687 were transplanted. Compared with the preceding era, there was significant decrease in death or deterioration in the last 2 eras (sub-hazard ratio, 0.67 [95% CI, 0.65-0.70] for Era 3 versus Era 2 and sub-hazard ratio, 0.65 [95% CI, 0.58-0.73] for Era 4 versus 3). Across the years, 27.1% to 40.5% of those on the waitlist were transplanted. Among those transplanted, there was increase in the rates of in-hospital stroke (2.8% in Era 1 to 3.7% in Era 4), renal failure requiring dialysis (7.2%-17.1%), and length-of-stay (14-17days), <0.001. However, this did not negatively impact short-term survival when compared with the preceding era (1-year graft survival from Era 1 to Era 4=84.1%, 86.4%, 90.4%, and 89.7%, respectively).

Conclusions: There have been significant changes in the characteristics of patients listed for heart transplantation. Although transplant volume has increased, the wide supply-demand gap persisted. The last two changes in the allocation policy achieved their primary objective of reducing waitlist mortality.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.121.008764DOI Listing
November 2021

Increased Access to Cardiac Surgery Did Not Improve Outcomes: Early Look Into Medicaid Expansion.

Ann Thorac Surg 2021 Oct 20. Epub 2021 Oct 20.

Division of Cardiothoracic Surgery, Rhode Island Hospital, Brown University Medical School, Providence, Rhode Island.

Background: Cardiac surgery utilization has increased after passage of the Affordable Care Act. This multistate study examined whether changes in access after Medicaid expansion (ME) have led to improved outcomes, overall and particularly among ethnoracial minorities.

Methods: State Inpatient Databases were used to identify nonelderly adults (ages 18-64 years) who underwent coronary artery bypass grafting, aortic valve replacement, mitral valve replacement, or mitral valve repair in 3 expansion (Kentucky, New Jersey, Maryland) vs 2 nonexpansion states (North Carolina, Florida) from 2012 to 2015. Linear and logistic interrupted time series were used with 2-way interactions and adjusted for patient-level, hospital-level, and county-level factors to compare trends and instantaneous changes at the point of ME implementation (quarter 1 of 2014) for mortality, length of stay, and elective status. Interrupted time series models estimated expansion effect, overall and by race-ethnicity.

Results: Analysis included 22 038 cardiac surgery patients from expansion states and 33 190 from nonexpansion states. In expansion states, no significant trend changes were observed for mortality (odds ratio, 1.01; P = .83) or length of stay (β = -0.05, P = .20), or for elective surgery (odds ratio, 1.00; P = .91). There were similar changes seen in nonexpansion states. Among ethnoracial minorities, ME did not impact outcomes or elective status.

Conclusions: Despite an increase in cardiac surgery utilization after ME, outcomes remained unchanged in the early period after implementation, overall and among ethnoracial minorities. Future research is needed to confirm long-term trends and examine reasons behind this lack of improved outcomes.
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http://dx.doi.org/10.1016/j.athoracsur.2021.09.025DOI Listing
October 2021

Commentary: If it looks too good to be true, it probably is.

Authors:
Frank W Sellke

JTCVS Tech 2021 Oct 1;9:93-94. Epub 2021 Jul 1.

Division of Cardiothoracic Surgery, Lifespan Cardiovascular Institute, Alpert Medical School of Brown University, and Rhode Island Hospital, Providence, RI.

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http://dx.doi.org/10.1016/j.xjtc.2021.06.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501201PMC
October 2021

The cardiac molecular setting of metabolic syndrome in pigs reveals disease susceptibility and suggests mechanisms that exacerbate COVID-19 outcomes in patients.

Sci Rep 2021 10 5;11(1):19752. Epub 2021 Oct 5.

Division of Cardiothoracic Surgery, Department of Surgery and, The Warren Alpert Medical School, Brown University, Providence, RI, 02903, USA.

Although metabolic syndrome (MetS) is linked to an elevated risk of cardiovascular disease (CVD), the cardiac-specific risk mechanism is unknown. Obesity, hypertension, and diabetes (all MetS components) are the most common form of CVD and represent risk factors for worse COVID-19 outcomes compared to their non MetS peers. Here, we use obese Yorkshire pigs as a highly relevant animal model of human MetS, where pigs develop the hallmarks of human MetS and reproducibly mimics the myocardial pathophysiology in patients. Myocardium-specific mass spectroscopy-derived metabolomics, proteomics, and transcriptomics enabled the identity and quality of proteins and metabolites to be investigated in the myocardium to greater depth. Myocardium-specific deregulation of pro-inflammatory markers, propensity for arterial thrombosis, and platelet aggregation was revealed by computational analysis of differentially enriched pathways between MetS and control animals. While key components of the complement pathway and the immune response to viruses are under expressed, key N6-methyladenosin RNA methylation enzymes are largely overexpressed in MetS. Blood tests do not capture the entirety of metabolic changes that the myocardium undergoes, making this analysis of greater value than blood component analysis alone. Our findings create data associations to further characterize the MetS myocardium and disease vulnerability, emphasize the need for a multimodal therapeutic approach, and suggests a mechanism for observed worse outcomes in MetS patients with COVID-19 comorbidity.
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http://dx.doi.org/10.1038/s41598-021-99143-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492658PMC
October 2021

Coronary Artery Bypass Grafting With the Internal Thoracic Artery: A Great Operation With Some Unanswered Questions.

Authors:
Frank W Sellke

JAMA Cardiol 2021 12;6(12):1362-1363

Division of Cardiothoracic Surgery, Alpert Medical School of Brown University, Providence, Rhode Island.

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http://dx.doi.org/10.1001/jamacardio.2021.3863DOI Listing
December 2021

probiotic induces Nrf2-mediated antioxidant signaling and eNOS expression resulting in improvement of myocardial diastolic function.

Am J Physiol Heart Circ Physiol 2021 11 10;321(5):H839-H849. Epub 2021 Sep 10.

Division of Cardiothoracic Surgery, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, Rhode Island.

Yorkshire swine were fed standard diet ( = 7) or standard diet containing applesauce rich in caffeic acid with ( = 7) for 3 wk. An ameroid constrictor was next placed around the left coronary circumflex artery, and the dietary regimens were continued. At 14 wk, cardiac function, myocardial perfusion, vascular density, and molecular signaling in ischemic myocardium were evaluated. The -applesauce augmented NF-E2-related factor 2 (Nrf2) in the ischemic myocardium and induced Nrf2-regulated antioxidant enzymes heme oxygenase-1 (HO-1), NADPH dehydrogenase quinone 1 (NQO-1), and thioredoxin reductase (TRXR-1). Improved left ventricular diastolic function and decreased myocardial collagen expression were seen in animals receiving the -applesauce supplements. The expression of endothelial nitric oxide synthase (eNOS) was increased in ischemic myocardial tissue of the treatment group, whereas levels of asymmetric dimethyl arginine (ADMA), hypoxia inducible factor 1α (HIF-1α), and phosphorylated MAPK (pMAPK) were decreased. Collateral-dependent myocardial perfusion was unaffected, whereas arteriolar and capillary densities were reduced as determined by α-smooth muscle cell actin and CD31 immunofluorescence in ischemic myocardial tissue. Dietary supplementation with -applesauce is a safe and effective method of enhancing Nrf2-mediated antioxidant signaling cascade in ischemic myocardium. Although this experimental diet was associated with a reduction in hypoxic stimuli, decreased vascular density, and without any change in collateral-dependent perfusion, the net effect of an increase in antioxidant activity and eNOS expression resulted in improvement in diastolic function. Colonization of the gut microbiome with certain strains of has been shown to convert caffeic acid readily available in applesauce to 4-vinyl-catechol, a potent activator of the Nrf2 antioxidant defense pathway. In this exciting study, we show that simple dietary supplementation with -applesauce-mediated Nrf2 activation supports vascular function, ameliorates myocardial ischemic diastolic dysfunction, and upregulates expression of eNOS.
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http://dx.doi.org/10.1152/ajpheart.00278.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616611PMC
November 2021

Medical malpractice in aortic valve and mitral valve replacement surgery in North America.

J Cardiovasc Surg (Torino) 2021 Aug 2. Epub 2021 Aug 2.

Warren Alpert Medical School, Brown University, Providence, RI, USA.

Background: Aortic and mitral valve replacement are commonly performed by cardiovascular surgeons, but little data quantitatively analyzes the etiology and prevalence of medical malpractice litigations involving these operations. This study aims to analyze incidence, cause, and resolution of medical malpractice lawsuits involving aortic and mitral valve replacements, alone and in combination with coronary artery bypass and/or aortic procedures.

Methods: The Westlaw legal database was utilized to compile relevant litigations across the United States from 1994-2019. Clinical data, verdict data, demographic data, and litigation attributes were compiled. Fisher-exact tests and Mann-Whitney tests were performed for statistical analyses.

Results: One hundred four malpractice litigations involving aortic valve replacement and 55 litigations involving mitral valve replacement were included in this analysis. The mean age of patients was 55.2 years and proportion of female patients was 32.7% in aortic valve replacements litigations, compared to a mean age of 54.1 years and female patients in 61.8% of mitral valve replacements litigations. Significant relationships exist between an alleged failure to monitor the patient and defendant verdicts (p=0.01), delayed treatment and defendant verdicts (p=0.04), and incidence of infective endocarditis and plaintiff verdicts (p=0.04) in aortic valve replacement litigations. Similarly, significant relationships exist between an alleged failure to diagnose and settlement verdicts (p=0.047), and stroke incidence and defendant verdicts (p=0.03) in mitral valve replacement litigations.

Conclusions: In addition to excellent surgeon patient/family communication, administering surgical treatment in a timely manner, diagnosing and acting on concomitant medical conditions, and close patient monitoring may diminish medical malpractice litigation involving aortic and mitral valve replacement operations.
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http://dx.doi.org/10.23736/S0021-9509.21.11945-7DOI Listing
August 2021

Inhibition of mitochondrial reactive oxygen species improves coronary endothelial function after cardioplegic hypoxia/reoxygenation.

J Thorac Cardiovasc Surg 2021 Jun 26. Epub 2021 Jun 26.

Division of Cardiothoracic Surgery, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI. Electronic address:

Objective: Cardioplegic ischemia-reperfusion and diabetes mellitus are correlated with coronary endothelial dysfunction and inactivation of small conductance calcium-activated potassium channels. Increased reactive oxidative species, such as mitochondrial reactive oxidative species, may contribute to oxidative injury. Thus, we hypothesized that inhibition of mitochondrial reactive oxidative species may protect coronary small conductance calcium-activated potassium channels and endothelial function against cardioplegic ischemia-reperfusion-induced injury.

Methods: Small coronary arteries and endothelial cells from the hearts of mice with and without diabetes mellitus were isolated and examined by using a cardioplegic hypoxia and reoxygenation model to determine whether the mitochondria-targeted antioxidant Mito-Tempo could protect against coronary endothelial and small conductance calcium-activated potassium channel dysfunction. The microvessels or mouse heart endothelial cells were treated with or without Mito-Tempo (0-10 μM) 5 minutes before and during cardioplegic hypoxia and reoxygenation. Microvascular function was assessed in vitro by vessel myography. K currents of mouse heart endothelial cells were measured by whole-cell patch clamp. The levels of intracellular cytosolic free calcium (Ca) concentration, mitochondrial reactive oxidative species, and small conductance calcium-activated potassium protein expression of mouse heart endothelial cells were measured by Rhod-2 fluorescence staining, MitoSox, and Western blotting, respectively.

Results: Cardioplegic hypoxia and reoxygenation significantly attenuated endothelial small conductance calcium-activated potassium channel activity, caused calcium overload, and increased mitochondrial reactive oxidative species of mouse heart endothelial cells in both the nondiabetic and diabetes mellitus groups. In addition, treating mouse heart endothelial cells with Mito-Tempo (10 μM) reduced cardioplegic hypoxia and reoxygenation-induced Ca and mitochondrial reactive oxidative species overload in both the nondiabetic and diabetes mellitus groups, respectively (P < .05). Treatment with Mito-Tempo (10 μM) significantly enhanced coronary relaxation responses to adenosine 5'-diphosphate and NS309 (P < .05), and endothelial small conductance calcium-activated potassium channel currents in both the nondiabetic and diabetes mellitus groups (P < .05).

Conclusions: Administration of Mito-Tempo improves endothelial function and small conductance calcium-activated potassium channel activity, which may contribute to its enhancement of endothelium-dependent vasorelaxation after cardioplegic hypoxia and reoxygenation.
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http://dx.doi.org/10.1016/j.jtcvs.2021.06.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8710187PMC
June 2021

Cardiac surgeons' concerns, perceptions, and responses during the COVID-19 pandemic.

J Card Surg 2021 Sep 12;36(9):3040-3051. Epub 2021 Jun 12.

Division of Cardiothoracic Surgery, UC Davis Medical Center, Sacramento, California, USA.

Background: The coronavirus disease 2019 (COVID-19) pandemic has had an unprecedented impact on health care and cardiac surgery. We report cardiac surgeons' concerns, perceptions, and responses during the COVID-19 pandemic.

Methods: A detailed survey was sent to recruit participating adult cardiac surgery centers in North America. Data regarding cardiac surgeons' perceptions and changes in practice were analyzed.

Results: Our study comprises 67 institutions with diverse geographic distribution across North America. Nurses were most likely to be redeployed (88%), followed by advanced care practitioners (69%), trainees (28%), and surgeons (25%). Examining surgeon concerns in regard to COVID-19, they were most worried with exposing their family to COVID-19 (81%), followed by contracting COVID-19 (68%), running out of personal protective equipment (PPE) (28%), and hospital resources (28%). In terms of PPE conservation strategies among users of N95 respirators, nearly half were recycling via decontamination with ultraviolet light (49%), followed by sterilization with heat (13%) and at home or with other modalities (13%). Reuse of N95 respirators for 1 day (22%), 1 week (21%) or 1 month (6%) was reported. There were differences in adoption of methods to conserve N95 respirators based on institutional pandemic phase and COVID-19 burden, with higher COVID-19 burden institutions more likely to resort to PPE conservation strategies.

Conclusions: The present study demonstrates the impact of COVID-19 on North American cardiac surgeons. Our study should stimulate further discussions to identify optimal solutions to improve workforce preparedness for subsequent surges, as well as facilitate the navigation of future healthcare crises.
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http://dx.doi.org/10.1111/jocs.15681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447333PMC
September 2021

International Scientific Collaboration Is Needed to Bridge Science to Society: USERN2020 Consensus Statement.

SN Compr Clin Med 2021 May 11:1-5. Epub 2021 May 11.

http://usern.org.

Scientific collaboration has been a critical aspect of the development of all fields of science, particularly clinical medicine. It is well understood that myriads of benefits can be yielded by interdisciplinary and international collaboration. For instance, our rapidly growing knowledge on COVID-19 and vaccine development could not be attained without expanded collaborative activities. However, achieving fruitful results requires mastering specific tactics in collaborative efforts. These activities can enhance our knowledge, which ultimately benefits society. In addition to tackling the issue of the invisible border between different countries, institutes, and disciplines, the border between the scientific community and society needs to be addressed as well. International and transdisciplinary approaches can potentially be the best solution for bridging science and society. The Universal Scientific Education and Research Network (USERN) is a non-governmental, non-profit organization and network to promote professional, scientific research and education worldwide. The fifth annual congress of USERN was held in Tehran, Iran, in a hybrid manner on November 7-10, 2020, with key aims of bridging science to society and facilitating borderless science. Among speakers of the congress, a group of top scientists unanimously agreed on The USERN 2020 consensus, which is drafted with the goal of connecting society with scientific scholars and facilitating international and interdisciplinary scientific activities in all fields, including clinical medicine.
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http://dx.doi.org/10.1007/s42399-021-00896-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111052PMC
May 2021

Medical malpractice in heart transplantation from 1994 to 2019.

J Card Surg 2021 Aug 12;36(8):2786-2790. Epub 2021 May 12.

Alpert Medical School, Brown University, Providence, Rhode Island, USA.

Background: Heart transplantation is a unique clinical intervention because it involves two separate parties, the donor and the recipient. This increases the potential for the legal liability of heart teams involved with heart transplantation, but there is no research that exists to date that analyzes the etiology of medical malpractice litigations relating to heart transplantation.

Methods: The Westlaw legal database was queried for all medical malpractice litigations concerning heart transplantation from 1994 to 2019 in the United States. Individual litigations were reviewed for inclusion, resulting in 41 included cases, and then analyzed for legal and clinical data. Statistical analyses were performed with the Fisher exact test and Mann-Whitney U tests.

Results: The mean age of patients involved in these litigations was 38.88 years, with female patients being younger on average. Female patients received a significantly larger average award than male counterparts (p = .03). Alleged failure to diagnose was significantly associated with settlements (p = .047). An alleged failure to obtain informed consent as presented by the plaintiff was significantly associated with defendant verdicts (p = .03). Incidence of stroke and infection were each significantly associated with nondefendant verdicts (p = .02 and p = .02).

Conclusions: There should be an emphasis on documenting informed consent from all involved parties in heart transplantation to limit litigations filed against clinicians. As technologies and growing donor pools increase the prevalence of heart transplantation, clinicians would be well-served to be aware of legally tenable practices that will allow them to adopt a higher transplant volume without simultaneously adopting added legal exposure.
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http://dx.doi.org/10.1111/jocs.15633DOI Listing
August 2021

Interdisciplinary Approaches to COVID-19.

Adv Exp Med Biol 2021 ;1318:923-936

Universal Scientific Education and Research Network (USERN), The World, Tehran, Iran.

The coronavirus disease 2019 (COVID-19) pandemic has been a significant concern worldwide. The pandemic has demonstrated that public health issues are not merely a health concern but also affect society as a whole. In this chapter, we address the importance of bringing together the world's scientists to find appropriate solutions for controlling and managing the COVID-19 pandemic. Interdisciplinary cooperation, through modern scientific methods, could help to handle the consequences of the pandemic and to avoid the recurrence of future pandemics.
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http://dx.doi.org/10.1007/978-3-030-63761-3_52DOI Listing
May 2021

Clinical Application of Novel Therapies for Coronary Angiogenesis: Overview, Challenges, and Prospects.

Int J Mol Sci 2021 Apr 2;22(7). Epub 2021 Apr 2.

Cardiovascular Research Center, Rhode Island Hospital, Providence, RI 02903, USA.

Cardiovascular diseases continue to be the leading cause of death worldwide, with ischemic heart disease as the most significant contributor. Pharmacological and surgical interventions have improved clinical outcomes, but are unable to ameliorate advanced stages of end-heart failure. Successful preclinical studies of new therapeutic modalities aimed at revascularization have shown short lasting to no effects in the clinical practice. This lack of success may be attributed to current challenges in patient selection, endpoint measurements, comorbidities, and delivery systems. Although challenges remain, the field of therapeutic angiogenesis is evolving, as novel strategies and bioengineering approaches emerge to optimize delivery and efficacy. Here, we describe the structure, vascularization, and regulation of the vascular system with particular attention to the endothelium. We proceed to discuss preclinical and clinical findings and present challenges and future prospects in the field.
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http://dx.doi.org/10.3390/ijms22073722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038234PMC
April 2021

Mesenchymal stem cell-derived extracellular vesicles in the failing heart: past, present, and future.

Am J Physiol Heart Circ Physiol 2021 05 16;320(5):H1999-H2010. Epub 2021 Apr 16.

Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island.

Cardiovascular disease (CVD) is the leading cause of death globally. Current treatment options include lifestyle changes, medication, and surgical intervention. However, many patients are unsuitable candidates for surgeries due to comorbidities, diffuse coronary artery disease, or advanced stages of heart failure. The search for new treatment options has recently transitioned from cell-based therapies to stem-cell-derived extracellular vesicles (EVs). A number of challenges remain in the EV field, including the effect of comorbidities, characterization, and delivery. However, recent revolutionary developments and insight into the potential of personalizing EV contents by bioengineering methods to alter specific signaling pathways in the ischemic myocardium hold promise. Here, we discuss the past limitations of cell-based therapies and recent EV studies involving in vivo, in vitro, and omics, and future challenges and opportunities in EV-based treatments in CVD.
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http://dx.doi.org/10.1152/ajpheart.00951.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163643PMC
May 2021

An Analysis of Medical Malpractice Litigations in Coronary Artery Bypass Grafting from 1994-2019.

Ann Thorac Surg 2022 Feb 29;113(2):600-607. Epub 2021 Mar 29.

Alpert Medical School, Brown University, Providence, Rhode Island; Division of Cardiothoracic Surgery, Rhode Island Hospital, Providence, Rhode Island.

Background: Cardiothoracic surgery is one of the more highly litigated medical specialties, and coronary artery bypass grafting (CABG) constitutes a substantial portion of cardiothoracic surgery cases. Therefore, understanding litigations relating to CABG would be of benefit to surgeons working to uphold the standards of care that their patients seek and minimize their own legal liability. This study analyzed CABG litigations to identify predictive factors of litigation and verdict type.

Methods: This study utilized the Westlaw legal database to compile litigations from 1994-2019 across the United States, and resulted in 307 total litigations. After individual screening, 211 litigations met the criteria for inclusion, and were analyzed for demographic, clinical, chronological, and verdict characteristics.

Results: Litigations were present in 33 US states, with California, New York, and Florida having the most litigations. Defendant verdicts were reached in 67.78% of litigations, followed by 20.38% of plaintiff verdicts, and 11.85% of settlements. Plaintiff verdicts were associated with the incidence of myocardial infarction during hospitalization. The winter season had the most litigations (42.18%), and the most defendant verdicts (37.76%). Patient mortality occurred in 47.39% of litigations. The most common alleged reason for litigation was a procedural error (55.45%).

Conclusions: Defendant verdicts were significantly associated with an alleged reason of procedural errors, an alleged reason of a failure to monitor, and congestive heart failure present in patients. The common nature of defendant verdicts, and the significantly greater occurrence of defendant verdicts during the highly litigated winter season, suggest that surgeons frequently satisfy the legal standard of care.
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http://dx.doi.org/10.1016/j.athoracsur.2021.03.042DOI Listing
February 2022

Chronic Inhibition of mROS Protects Against Coronary Endothelial Dysfunction in Mice With Diabetes.

Front Cell Dev Biol 2021 18;9:643810. Epub 2021 Feb 18.

Cardiothoracic Surgery Research Laboratory, Cardiovascular Research Center, Department of Surgery, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, United States.

Diabetes is associated with coronary endothelial dysfunction. Persistent oxidative stress during diabetes contributes to coronary endothelial dysfunction. The mitochondria are main sources of reactive oxygen species (ROS) in diabetes, and mitochondria-targeted antioxidant mito-Tempo can prevent mitochondrial reactive oxygen species (mROS) generation in a variety of disorders. Inhibition/inactivation of small-conductance Ca-activated K (SK) channels contribute to diabetic downregulation of coronary endothelial function/relaxation. However, few investigated the role of mROS on endothelial dysfunction/vasodilation and endothelial SK channel downregulation in diabetes. The aim of present study was to investigate the chronic administration of mito-Tempo, on coronary vasodilation, and endothelial SK channel activity of mice with or without diabetes. Mito-Tempo (1 mg/kg/day) was applied to the mice with or without diabetes ( = 10/group) for 4 weeks. relaxation response of pre-contracted arteries was examined in the presence or absence of the vasodilatory agents. SK channel currents of the isolated mouse heart endothelial cells were measured using whole-cell patch clamp methods. At baseline, coronary endothelium-dependent relaxation responses to ADP and the selective SK channel activator NS309 and endothelial SK channel currents were decreased in diabetic mice compared with that in non-diabetic (ND) mice ( < 0.05). After a 4-week treatment with mito-Tempo, coronary endothelium-dependent relaxation response to ADP or NS309 and endothelial SK channel currents in the diabetic mice was significantly improved when compared with that in untreated diabetic mice ( < 0.05). Interestingly, coronary relaxation responses to ADP and NS309 and endothelial SK channel currents were not significantly changed in ND mice after mito-Tempo treatment, as compared to that of untreated control group. Chronic inhibition of endothelial mROS appears to improve coronary endothelial function/dilation and SK channel activity in diabetes, and mROS inhibitors may be a novel strategy to treat vascular complications in diabetes.
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http://dx.doi.org/10.3389/fcell.2021.643810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930489PMC
February 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021
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