Publications by authors named "Victor Pretorius"

81 Publications

AI-guided discovery of the invariant host response to viral pandemics.

EBioMedicine 2021 Jun 11:103390. Epub 2021 Jun 11.

Moores Cancer Center, University of California San Diego, USA; Department of Cellular and Molecular Medicine, University of California San Diego, USA; Medicine, University of California San Diego, USA. Electronic address:

Background: Coronavirus Disease 2019 (Covid-19) continues to challenge the limits of our knowledge and our healthcare system. Here we sought to define the host immune response, a.k.a, the "cytokine storm" that has been implicated in fatal COVID-19 using an AI-based approach.

Method: Over 45,000 transcriptomic datasets of viral pandemics were analyzed to extract a 166-gene signature using ACE2 as a 'seed' gene; ACE2 was rationalized because it encodes the receptor that facilitates the entry of SARS-CoV-2 (the virus that causes COVID-19) into host cells. An AI-based approach was used to explore the utility of the signature in navigating the uncharted territory of Covid-19, setting therapeutic goals, and finding therapeutic solutions.

Findings: The 166-gene signature was surprisingly conserved across all viral pandemics, including COVID-19, and a subset of 20-genes classified disease severity, inspiring the nomenclatures ViP and severe-ViP signatures, respectively. The ViP signatures pinpointed a paradoxical phenomenon wherein lung epithelial and myeloid cells mount an IL15 cytokine storm, and epithelial and NK cell senescence and apoptosis determine severity/fatality. Precise therapeutic goals could be formulated; these goals were met in high-dose SARS-CoV-2-challenged hamsters using either neutralizing antibodies that abrogate SARS-CoV-2•ACE2 engagement or a directly acting antiviral agent, EIDD-2801. IL15/IL15RA were elevated in the lungs of patients with fatal disease, and plasma levels of the cytokine prognosticated disease severity.

Interpretation: The ViP signatures provide a quantitative and qualitative framework for titrating the immune response in viral pandemics and may serve as a powerful unbiased tool to rapidly assess disease severity and vet candidate drugs.

Funding: This work was supported by the National Institutes for Health (NIH) [grants CA151673 and GM138385 (to DS) and AI141630 (to P.G), DK107585-05S1 (SD) and AI155696 (to P.G, D.S and S.D), U19-AI142742 (to S.

C, Cchi: Cooperative Centers for Human Immunology)]; Research Grants Program Office (RGPO) from the University of California Office of the President (UCOP) (R00RG2628 & R00RG2642 to P.G, D.S and S.D); the UC San Diego Sanford Stem Cell Clinical Center (to P.G, D.S and S.D); LJI Institutional Funds (to S.C); the VA San Diego Healthcare System Institutional funds (to L.C.A). GDK was supported through The American Association of Immunologists Intersect Fellowship Program for Computational Scientists and Immunologists.

One Sentence Summary: The host immune response in COVID-19.
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http://dx.doi.org/10.1016/j.ebiom.2021.103390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193764PMC
June 2021

An Adapted Process and Organ Procurement Perspective on Heart Retransplantation for a Healthy Heart's Third Life.

Prog Transplant 2021 Jun 11:15269248211024616. Epub 2021 Jun 11.

University of California San Diego, San Diego, CA, USA.

As organ procurement organizations nationwide see an increased opportunity to retransplant already transplanted hearts, we would like to share the overview and process of our 2 successful cases. Heart retransplantation increased our cardiac placement rates by 2.64% and 2% in 2015 and 2019, respectively. Spread across a nation that sees over 3500 heart placements annually, a 2% increase would be substantial. Since 2009, our cases stand as the only documented heart retransplantations in the United States. However, United Network for Organ Sharing data shows that potential exists. From a facilitation perspective, we have developed a protocol to ease the matching process. From a surgical perspective, these cases had no complications and saved 2 lives, with each heart now beating in a third person. We hope that by sharing our process and success, we can familiarize fellow organ procurement organizations and transplant communities with this viable opportunity.
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http://dx.doi.org/10.1177/15269248211024616DOI Listing
June 2021

What goes in may need to come out: Considerations in the extraction of a lumenless, fixed-screw permanent pacemaker lead.

Heart Rhythm O2 2020 Jun 11;1(2):160-163. Epub 2020 May 11.

Department of Cardiac Electrophysiology, University of California San Diego Medical Center, La Jolla, California.

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http://dx.doi.org/10.1016/j.hroo.2020.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183842PMC
June 2020

Increased peripheral blood neutrophil activation phenotypes and NETosis in critically ill COVID-19 patients: a case series and review of the literature.

Clin Infect Dis 2021 May 14. Epub 2021 May 14.

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA.

Background: Increased inflammation has been well defined in COVID-19, while definitive pathways driving severe forms of this disease remain uncertain. Neutrophils are known to contribute to immunopathology in infections, inflammatory diseases and acute respiratory distress syndrome (ARDS), a primary cause of morbidity and mortality in COVID-19. Changes in neutrophil function in COVID-19 may give insight into disease pathogenesis and identify therapeutic targets.

Methods: Blood was obtained serially from critically ill COVID-19 patients for eleven days. Neutrophil extracellular trap formation (NETosis), oxidative burst, phagocytosis and cytokine levels were assessed. Lung tissue was obtained immediately post-mortem for immunostaining. Pubmed searches for neutrophils, lung and COVID-19 yielded ten peer-reviewed research articles in English.

Results: Elevations in neutrophil-associated cytokines IL-8 and IL-6, and general inflammatory cytokines IP-10, GM-CSF, IL-1b, IL-10 and TNF, were identified both at first measurement and across hospitalization (p<0.0001). COVID neutrophils had exaggerated oxidative burst (p<0.0001), NETosis (p<0.0001) and phagocytosis (p<0.0001) relative to controls. Increased NETosis correlated with leukocytosis and neutrophilia, and neutrophils and NETs were identified within airways and alveoli in lung parenchyma of 40% of SARS-CoV-2 infected lungs available for examination (2 out of 5). While elevations in IL-8 and ANC correlated with disease severity, plasma IL-8 levels alone correlated with death.

Conclusions: Literature to date demonstrates compelling evidence of increased neutrophils in the circulation and lungs of COVID-19 patients. importantly, neutrophil quantity and activation correlates with severity of disease. Similarly, our data shows that circulating neutrophils in COVID-19 exhibit an activated phenotype with enhanced NETosis and oxidative burst.
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http://dx.doi.org/10.1093/cid/ciab437DOI Listing
May 2021

Clinical significance of incidentally detected lead perforations by computed tomography.

Pacing Clin Electrophysiol 2021 May 9;44(5):936-942. Epub 2021 Apr 9.

Division of Cardiology, Department of Medicine, University of California San Diego, La Jolla, California, USA.

Background: Computed tomography (CT) has an established role in detecting perforation of implanted pacemaker and defibrillator leads. The clinical significance of incidental finding of delayed lead perforation remains unclear. The aim of this study was to assess the prevalence of lead perforation as detected by CT in a cohort of patients undergoing transvenous laser lead extraction and characterize the association between finding of incidental lead perforation with periprocedural outcomes.

Methods: Consecutive patients that underwent chest CT and lead extraction were retrospectively assessed for presence of lead perforation. A total of 143 patients and 348 leads were assessed. The finding of lead perforation was correlated with findings from peri-procedural transesophageal echocardiography (TEE) and outcomes of the lead extraction procedure.

Results: Lead perforations (including perforations <5 mm and ≥5 mm) were detected in 66 (46%) patients and 73 (21%) leads. Lead perforation ≥5 mm were less common and detected in 13 (9%) of patients and 14 (4%) of leads. There was no significant difference in the rates of peri-procedural death, cardiac avulsion, cardiac tamponade or post-extraction pericardial effusion in patients with and without lead perforation.

Conclusions: Incidental delayed lead perforations detected by CT are common and do not correlate with significant TEE findings or adverse peri-procedural outcomes in patients undergoing lead extraction. Larger studies are needed to further characterize the frequency and safety of these findings.
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http://dx.doi.org/10.1111/pace.14229DOI Listing
May 2021

Safety and Efficacy of Cardiovascular Implantable Electronic Device Extraction in Elderly Patients: A Meta-Analysis and Systematic Review.

Heart Rhythm O2 2020 Oct 4;1(4):250-258. Epub 2020 Aug 4.

Division of Cardiology, University of California San Diego, La Jolla, California.

Background: Transvenous lead extraction of cardiovascular implantable electronic device (CIED) has been proven safe in the general patient population with the advances in extraction techniques. Octogenarians present a unique challenge given their comorbidities and the perceived increase in morbidity and mortality.

Objective: To assess the safety and outcomes of CIED extraction in octogenarians to younger patients.

Methods: We performed an extensive literature search and systematic review of studies that compared CIED extraction in octogenarians versus non-octogenarians. We separately assessed the rate of complete procedure success, clinical success, procedural mortality, major and minor complications. Risk ratio (RR) 95% confidence intervals were measured using the Mantel-Haenszel method. The random effects model was used due to heterogeneity across study cohorts.

Results: Seven studies with a total of 4,182 patients were included. There was no difference between octogenarians and non-octogenarians in complete procedure success (RR 1.01, 95% CI 1.00 - 1.02, p = 0.19) and clinical success (RR 1.01, 95% CI 1.00 - 1.01, p = 0.13). There was also no difference in procedural mortality (RR 1.43, 95% CI 0.46 - 4.39, p = 0.54), major complication (RR 1.40, 95% CI 0.68 - 2.88, p = 0.36), and minor complication (RR 1.43, 95% CI 0.90 - 2.29, p = 0.13).

Conclusion: In this study, there was no evidence to suggest a difference in procedural success and complication rates between octogenarians and younger patients. Transvenous lead extraction can be performed safely and effectively in the elderly population.
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http://dx.doi.org/10.1016/j.hroo.2020.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889020PMC
October 2020

A Case of CIED-Associated Endocarditis and Septic Emboli Requiring Lead Extraction, AngioVac Suction, and Pulmonary Endarterectomy.

Cureus 2020 Nov 20;12(11):e11601. Epub 2020 Nov 20.

Cardiothoracic Surgery, University of California San Diego School of Medicine, La Jolla, USA.

Cardiac Implantable Electronic Devices (CIED)-associated infective endocarditis complicated by septic emboli and acute on chronic pulmonary hypertension is rare. We present a case where pulmonary thromboendarterectomy was required for treatment. A 55 year-old man with a history of myocardial infarction and ischemic cardiomyopathy status-post ICD placement 8 years prior presented with bacteremia, infected ICD, and tricuspid valve vegetation. He underwent CIED extraction along with the use of the AngioVac suction device to remove right ventricular and atrial vegetations. However the patient had persistent valvular vegetation and bilateral sub-massive pulmonary emboli. Pulmonary angiography showed filling defects in the lobar and segmental arteries. Percutaneous attempts at embolectomy were unsuccessful and he therefore underwent a pulmonary endarterectomy surgery (PTE). This case of CIED- associated endocarditis demonstrates the importance of early aggressive treatment of such infections. Guidelines recommend compete CIED system removal when there is associated infection. The AngioVac is a novel system for removal of right-sided vegetations and thrombi; however, complications such as distal embolization can occur. PTE surgery for septic emboli is rare. However, cases of such treatment as is presented here can be successful and may be necessary should percutaneous methods fail.
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http://dx.doi.org/10.7759/cureus.11601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752741PMC
November 2020

Early Versus Delayed Lead Extraction in Patients With Infected Cardiovascular Implantable Electronic Devices.

JACC Clin Electrophysiol 2020 Dec 17. Epub 2020 Dec 17.

Division of Cardiology, University of California, San Diego, La Jolla, California, USA.

Objectives: This study sought to assess the impact of early versus delayed lead extraction in patients with an infected cardiovascular implantable electronic device (CIED).

Background: CIED infections are associated with poor outcomes. Prior studies have demonstrated improved survival with CIED extraction compared with antibiotic therapy alone. The impact of timing of CIED extraction has not been well characterized.

Methods: All infected CIED extraction cases at our medical center from 2006 to 2019 were reviewed. Patients were divided into 2 groups based on the presence of bacteremia or isolated pocket infection. We assessed the in-hospital morbidity and 1-year mortality for early versus delayed lead extraction, using hospitalization day 7 as cutoff.

Results: Of 233 patients who underwent CIED extraction, 127 patients had bacteremia and 106 patients had pocket infection. Delayed extraction (15.2 days) in bacteremic patients was associated with septic shock (odds ratio [OR]: 5.39; 95% confidence interval [CI]: 1.23 to 23.67; p = 0.026), acute kidney injury (OR: 5.61; 95% CI: 2.15 to 14.63; p < 0.001), respiratory failure (OR: 5.52; 95% CI: 1.25 to 24.41; p = 0.024), and decompensated heart failure (OR: 3.32; 95% CI: 1.10 to 10.05; p = 0.033). Locally infected patients with delayed extraction (10.7 days) were associated with acute kidney injury (OR: 3.45; 95% CI: 1.11 to 10.77; p = 0.033) and respiratory failure (OR: 10.29; 95% CI: 1.26 to 83.93; p = 0.030). Delayed CIED extraction in both groups was associated with increased 1-year mortality.

Conclusions: Delayed infected CIED extraction is associated with worse outcomes. This underscores the importance of early detection and a strategy for prompt management including lead extraction.
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http://dx.doi.org/10.1016/j.jacep.2020.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209117PMC
December 2020

Successful Concomitant Pulmonary Thromboendarterectomy and Heart Transplant.

Ann Thorac Surg 2021 Jun 17;111(6):e421-e423. Epub 2020 Dec 17.

Department of Cardiothoracic Surgery, University of California San Diego, La Jolla, California.

Heart transplantation remains the gold standard of therapy for patients with end-stage heart failure. Submassive pulmonary embolism in a patient with heart failure is generally considered a contraindication to immediate heart transplantation, given the risk of right heart failure posttransplant. Generally patients must wait for extended periods of time to recover from pulmonary embolism therapies before being listed for transplant. We report a case of successful concomitant pulmonary thromboendarterectomy and heart transplantation.
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http://dx.doi.org/10.1016/j.athoracsur.2020.09.065DOI Listing
June 2021

AI-guided discovery of the invariant host response to viral pandemics.

bioRxiv 2020 Sep 22. Epub 2020 Sep 22.

We sought to define the host immune response, a.k.a, the "cytokine storm" that has been implicated in fatal COVID-19 using an AI-based approach. Over 45,000 transcriptomic datasets of viral pandemics were analyzed to extract a 166-gene signature using ACE2 as a 'seed' gene; ACE2 was rationalized because it encodes the receptor that facilitates the entry of SARS-CoV-2 (the virus that causes COVID-19) into host cells. Surprisingly, this 166-gene signature was conserved in all ral andemics, including COVID-19, and a subset of 20-genes classified disease severity, inspiring the nomenclatures and signatures, respectively. The signatures pinpointed a paradoxical phenomenon wherein lung epithelial and myeloid cells mount an IL15 cytokine storm, and epithelial and NK cell senescence and apoptosis determines severity/fatality. Precise therapeutic goals were formulated and subsequently validated in high-dose SARS-CoV-2-challenged hamsters using neutralizing antibodies that abrogate SARS-CoV-2•ACE2 engagement. IL15/IL15RA were elevated in the lungs of patients with fatal disease, and plasma levels of the cytokine tracked with disease severity. Thus, the signatures provide a quantitative and qualitative framework for titrating the immune response in viral pandemics and may serve as a powerful unbiased tool to rapidly assess disease severity and vet candidate drugs.

One Sentence Summary: The host immune response in COVID-19.
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http://dx.doi.org/10.1101/2020.09.21.305698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523116PMC
September 2020

Outcome of patients on heart transplant list treated with a continuous-flow left ventricular assist device: Insights from the TRans-Atlantic registry on VAd and TrAnsplant (TRAViATA).

Int J Cardiol 2021 02 18;324:122-130. Epub 2020 Sep 18.

University Hospital, Leuven, Belgium.

Background: Geographic variations in management and outcomes of individuals supported by continuous-flow left ventricular assist devices (CF-LVAD) between the United States (US) and Europe (EU) is largely unknown.

Methods: We created a retrospective, multinational registry of 524 patients who received a CF-LVAD (either HVAD or Heartmate II) between January 2008 and April 2017. Follow up spanned from date of CF-LVAD implant to post-HTx period with a median follow up of 44.8 months.

Results: The cohort included 299 (57.1%) EU and 225 (42.9%) US patients. Although the US cohort was significantly older with a higher prevalence of comorbidities, survival was similar between the cohorts (US 63.1%, EU 68.4% at 5 years, unadjusted log-rank test p = 0.43).Multivariate analyses suggested that older age, higher body mass index, elevated creatinine, use of temporary mechanical circulatory support prior CF-LVAD, and implantation of HVAD were associated with increased mortality. Among CF-LVAD patients undergoing HTx, the median time on CF-LVAD support was shorter in the US, meanwhile US donors were younger. Finally, the pattern of adverse events (stroke, gastrointestinal bleedings, late right ventricular failure, and driveline infection) during support differed significantly between US and EU.

Conclusions: Although waitlisted patients in the US on CF-LVAD have higher risk comorbid conditions, the overall outcome is similar in US and EU. Geographic variations with regards to donor characteristics, duration of CF-LVAD support prior to transplant, and adverse events on support can explain the disparity in the utilization of mechanical bridge to transplant strategy between US and EU.
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http://dx.doi.org/10.1016/j.ijcard.2020.09.026DOI Listing
February 2021

Evaluation of Routine Coronary Angiography Before Pulmonary Thromboendarterectomy.

Ann Thorac Surg 2021 05 5;111(5):1703-1709. Epub 2020 Sep 5.

Division of Cardiovascular Medicine, University of California, San Diego, La Jolla, California. Electronic address:

Background: At the University of California, San Diego, routine coronary angiography has generally been performed in men 40 years of age and older and women 45 years of age and older before pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension (CTEPH). The prevalence of significant coronary artery disease (CAD) in this population has not been evaluated, however, and the optimal screening strategy has not been established. This study sought to evaluate whether the current approach may be better optimized on the basis of cardiac risk factors.

Methods: This study included 462 consecutive patients with CTEPH who were undergoing preoperative coronary angiography for pulmonary thromboendarterectomy. Baseline demographic and medical information was recorded. Major cardiac risk factors included: diabetes, hypertension, hyperlipidemia, body mass index 25 kg/m or greater, tobacco use, and family history of CAD. Charts were then reviewed for presence of significant CAD and revascularization.

Results: Significant CAD was found in 13.4% of patients who underwent routine preoperative coronary angiography; it was present in only 5% of patients younger than 50 years of age, compared with 16% of patients 50 years old and older. No patient younger than 50 years of age without cardiac risk factors was found to have significant CAD. Furthermore, in patients younger than 50 years of age, significant CAD was found only among those with 3 or more major risk factors.

Conclusions: In patients younger than 50 years of age with CTEPH, the prevalence of significant CAD was low. Omitting preoperative coronary angiography in this subset of patients is reasonable when no coronary risk factors are present. Preoperative coronary angiography is warranted in individuals 50 years of age and older, as well as in those younger than 50 years who have significant risk factors for CAD.
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http://dx.doi.org/10.1016/j.athoracsur.2020.06.107DOI Listing
May 2021

Cost-effectiveness of using hepatitis C viremic hearts for transplantation into HCV-negative recipients.

Am J Transplant 2021 02 15;21(2):657-668. Epub 2020 Sep 15.

Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, La Jolla, California.

Outcomes following hepatitis C virus (HCV)-viremic heart transplantation into HCV-negative recipients with HCV treatment are good. We assessed cost-effectiveness between cohorts of transplant recipients willing and unwilling to receive HCV-viremic hearts. Markov model simulated long-term outcomes among HCV-negative patients on the transplant waitlist. We compared costs (2018 USD) and health outcomes (quality-adjusted life-years, QALYs) between cohorts willing to accept any heart and those willing to accept only HCV-negative hearts. We assumed 4.9% HCV-viremic donor prevalence. Patients receiving HCV-viremic hearts were treated, assuming $39 600/treatment with 95% cure. Incremental cost-effectiveness ratios (ICERs) were compared to a $100 000/QALY gained willingness-to-pay threshold. Sensitivity analyses included stratification by blood type or region and potential negative consequences of receipt of HCV-viremic hearts. Compared to accepting only HCV-negative hearts, accepting any heart gained 0.14 life-years and 0.11 QALYs, while increasing costs by $9418/patient. Accepting any heart was cost effective (ICER $85 602/QALY gained). Results were robust to all transplant regions and blood types, except type AB. Accepting any heart remained cost effective provided posttransplant mortality and costs among those receiving HCV-viremic hearts were not >7% higher compared to HCV-negative hearts. Willingness to accept HCV-viremic hearts for transplantation into HCV-negative recipients is cost effective and improves clinical outcomes.
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http://dx.doi.org/10.1111/ajt.16245DOI Listing
February 2021

The Risk of Malposition: A Tale of Two Devices.

J Cardiothorac Vasc Anesth 2021 Mar 10;35(3):963-966. Epub 2020 Jul 10.

University of California, San Diego, UCSD Medical Center, La Jolla, CA.

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http://dx.doi.org/10.1053/j.jvca.2020.07.018DOI Listing
March 2021

Post-transplant survey to assess patient experiences with donor-derived HCV infection.

Transpl Infect Dis 2020 Dec 23;22(6):e13402. Epub 2020 Jul 23.

Department of Medicine, University of California, San Diego, California, USA.

Background: Despite increased utilization of hepatitis C virus-infected (HCV+) organs for transplantation into HCV-uninfected recipients, there is lack of standardization in HCV-related patient education/consent and limited data on financial and social impact on patients.

Methods: We conducted a survey on patients with donor-derived HCV infection at our center transplanted between 4/1/2017 and 11/1/2019 to assess: why patients chose to accept HCV+ organ(s), the adequacy of their pre-transplant HCV education and informed consent process, financial issues related to copays after discharge, and social challenges they faced.

Results: Among 49 patients surveyed, transplanted organs included heart (n = 19), lung (n = 9), kidney (n = 11), liver (n = 4), heart/kidney (n = 4), and liver/kidney (n = 2). Many recipients accepted an HCV-viremic (HCV-V) organ due to perceived reduction in waitlist time (n = 33) and/or trust in their physician's recommendation (n = 29). Almost all (n = 47) felt that pre-transplant education and consent was appropriate. Thirty patients had no copay for direct-acting antivirals (DAA) for HCV, including 21 with household income <$20 000; seven had copays of <$100 and one had a copay >$1000. Two patients reported feeling isolated due to HCV infection and eight reported higher than anticipated medication costs. Patients' biggest concern was potential HCV transmission to partners (n = 18) and family/friends (n = 15). Overall almost all (n = 47) patients reported a positive experience with HCV-V organ transplantation.

Conclusion: We demonstrate that real-world patient experiences surrounding HCV-V organ transplantation have been favorable. Almost all patients report comprehensive HCV-related pre-transplant consent and education. Additionally, medication costs and social isolation/exclusion were not barriers to the use of these organs.
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http://dx.doi.org/10.1111/tid.13402DOI Listing
December 2020

Persistence of the Dilemma: Inability to Detect a Persistent Left Superior Vena Cava Using Standard Echocardiographic Criteria.

J Cardiothorac Vasc Anesth 2021 01 12;35(1):357-360. Epub 2020 Jun 12.

Division of Cardiothoracic Anesthesia, Department of Anesthesiology, Sulpizio Cardiovascular Center at UC San Diego Health, La Jolla, CA.

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http://dx.doi.org/10.1053/j.jvca.2020.06.004DOI Listing
January 2021

Significance of Aortopulmonary Collaterals in a Single-Ventricle Patient Supported With a HeartMate 3.

Circ Heart Fail 2020 04 6;13(4):e006473. Epub 2020 Apr 6.

Division of Cardiovascular Medicine (R.R.R., J.S.E., L.A., E.D.A., M.A.U.), University of California San Diego.

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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006473DOI Listing
April 2020

Cost of Thoracotomy Approach: An Analysis of the LATERAL Trial.

Ann Thorac Surg 2020 11 26;110(5):1512-1519. Epub 2020 Mar 26.

Department of Cardiothoracic Surgery, Newark Beth Israel Medical Center, Newark, New Jersey.

Background: Less invasive techniques for left ventricular assist device implantation have been increasingly prevalent over past years and have been associated with improved clinical outcomes. The procedural economic impact of these techniques remains unknown. We sought to study and report economic outcomes associated with the thoracotomy implantation approach.

Methods: The LATERAL clinical trial evaluated the safety and efficacy of the thoracotomy approach for implantation of the HeartWare centrifugal-flow ventricular assist device system (HVAD). We collected UB-04 forms in parallel to the trial, allowing analysis of index hospitalization costs. All charges were converted to costs using hospital-specific cost-to-charge ratios and were subsequently compared with Medicare cost data for the same period (2015-2016). Because thoracotomy implants were off-label for all left ventricular assist devices during that period, the Medicare cohort was assumed to consist predominately of traditional sternotomy patients.

Results: Thoracotomy patients demonstrated decreased costs compared with sternotomy patients during the index hospitalization. Mean total index hospitalization costs for thoracotomy were $204,107 per patient, corresponding to 21.6% reduction (P < .001) and $56,385 savings per procedure compared with sternotomy. Across almost all cost categories, thoracotomy implants were less costly.

Conclusions: In LATERAL, a clinical trial evaluating the safety and efficacy of the thoracotomy approach for HVAD, costs were lower than those reported in Medicare patient claims occurring over the same period. Because Medicare data can be presumed to consist of predominately sternotomy procedures, thoracotomy appears less expensive than traditional sternotomy.
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http://dx.doi.org/10.1016/j.athoracsur.2020.02.047DOI Listing
November 2020

Local and regional variability in utilization and allocation of hepatitis C virus-infected hearts for transplantation.

Am J Transplant 2020 10 10;20(10):2867-2875. Epub 2020 Apr 10.

Division of Infectious Diseases, University of California, San Diego, California, USA.

With the advent of direct-acting antiviral agents, there has been a rapid rise in hepatitis C virus-infected (HCV+) heart transplantation. We aimed to understand local and regional differences in utilization and allocation of HCV+ hearts. Using United Network for Organ Sharing (UNOS) de-identified data from January 1, 2016 to September 30, 2019 we compared trends in the utilization rates (hearts transplanted/donors recovered) of HCV-uninfected (HCV-) to those of HCV+ nonviremic (HCV-NV) and viremic (HCV-V) hearts nationally and by UNOS region. We also evaluated allocation rates (hearts successfully allocated/donors recovered) by organ procurement organization (OPO). We found that (1) in 2019, national utilization rates for HCV-NV and HCV-V hearts were the same as HCV- hearts (27.6% for HCV-NV, 30.9 for HCV-V, and 31.7% for HCV-, P = .277); (2) utilization rates of HCV-NV hearts were low in regions 3 and 4 and of HCV-V hearts in regions 3, 4, and 8 even in the contemporary period since 2018; and (3) there was marked variability in allocation of HCV+ hearts at the OPO level even within the same UNOS region. We conclude that despite national strides in the utilization of HCV+ hearts for transplantation, more aggressive allocation of HCV+ hearts at the OPO level may still significantly affect the organ shortage.
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http://dx.doi.org/10.1111/ajt.15857DOI Listing
October 2020

Computed Tomography-Guided Risk Assessment in Percutaneous Lead Extraction.

JACC Clin Electrophysiol 2019 12 27;5(12):1439-1446. Epub 2019 Nov 27.

Division of Cardiology, Department of Medicine, University of California San Diego, La Jolla, California.

Objectives: The aim of this study was to assess if pre-procedural computed tomography (CT) could identify high-risk operative features and predict increased procedural complexity.

Background: Unpredictable lead adhesions can make lead extraction complicated. Adhesions are known to affect leads with longer indwelling time but can unpredictably affect newer leads.

Methods: Consecutive patients who had CTs performed ≤90 days before their planned lead extraction (LE) were included. CTs were reviewed blinded to outcome according to a preset checklist. The outcome was a combined endpoint of procedural complexity and major complications.

Results: Between January 1, 2015 and July 1, 2018, 143 patients underwent CT and LE. Median age was 68 years (interquartile range [IQR]: 54.4 to 76.5), and 35% were female. Median age of extracted leads was 111 months, and 126 (43%) were >10 years. CT detected lead perforation ≥5 mm (n = 13), <5 mm (n = 55), severe lead adhesions (n = 65), leads touching vessel wall >1 cm (n = 102), lead fracture (n = 8), and severe ipsilateral venous stenosis/occlusion (n = 36). The procedure was complex in 63 cases. There were 2 deaths, and 6 major complications. Patients with severe lead adhesions had more complex procedures (n = 36 vs 29; p = 0.04), whereas none of the other findings on CT were significantly associated with worse outcome. In patients with leads that had an indwelling time <10 years (n = 72), severe lead adhesions on CT was associated with worse outcome in multivariable analysis (odds ratio: 6.4; 95% confidence interval: 1.4 to 30.2; p = 0.02).

Conclusions: Pre-procedural CT can be used to locate severe lead adhesions in patients planned for lead extraction. In patients with indwelling leads <10 years, pre-procedural CT aids in identifying patients prone to complex extractions.
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http://dx.doi.org/10.1016/j.jacep.2019.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718020PMC
December 2019

Ventricular arrhythmias in patients with biventricular assist devices.

J Interv Card Electrophysiol 2020 Sep 14;58(3):243-252. Epub 2019 Dec 14.

Division of Cardiology, Department of Medicine, Cardiovascular Institute, University of California San Diego, 9452 Medical Center Dr. MC 7411, La Jolla, CA, 92037, USA.

Purpose: Ventricular arrhythmias (VAs) are common in patients after left ventricular assist device (LVAD) implant and are associated with worse outcomes. However, the prevalence and impact of VA in patients with durable biventricular assist device (BIVAD) is unknown. We performed a retrospective cohort study of patients with BIVADs to evaluate the prevalence of VA and their clinical outcomes.

Methods: Consecutive patients who received a BIVAD between June 2014 and July 2017 at our medical center were included. The prevalence of VA, defined as sustained ventricular tachycardia or fibrillation requiring defibrillation or ICD therapy, was compared between BIVAD patients and a propensity-matched population of patients with LVAD from our center. The occurrence of adverse clinical events was compared between BIVAD patients with and without VA.

Results: Of the 13 patients with BIVADs, 6 patients (46%) experienced clinically significant VA, similar to a propensity-matched LVAD population (38%, p = 1.00). There were no differences in baseline characteristics between the two cohorts, except patients in the non-VA group who had worse hemodynamics (mitral regurgitation and right-sided indices), had less history of VA, and were younger. BIVAD patients with VA had a higher incidence of major bleeding (MR 3.05 (1.07-8.66), p = 0.036) and worse composite outcomes (log-rank test, p = 0.046). The presence of VA was associated with worse outcomes in both LVAD and BIVAD groups.

Conclusions: Ventricular arrhythmias are common in patients with BIVADs and are associated with worse outcomes. Future work should assess whether therapies such as ablation improve the outcome of BIVAD patients with VA.
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http://dx.doi.org/10.1007/s10840-019-00682-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293581PMC
September 2020

Novel Use of Cangrelor With Heparin During Cardiopulmonary Bypass in Patients With Heparin-Induced Thrombocytopenia Who Require Cardiovascular Surgery: A Case Series.

Semin Thorac Cardiovasc Surg 2020 Winter;32(4):763-769. Epub 2019 Oct 11.

Division of Cardiothoracic Surgery, University of California San Diego, Sulpizio Cardiovascular Center, La Jolla, California.

Optimal anticoagulation strategy during cardiopulmonary bypass (CPB) remains uncertain in patients with heparin-induced thrombocytopenia (HIT) who require urgent/emergent cardiac surgery. We describe our strategy and experience with utilizing cangrelor in combination with heparin for anticoagulation during CPB in patients with different phases of HIT undergoing a wide range of urgent/emergent cardiovascular surgery. Cangrelor is an intravenous direct-acting P2Y12 platelet receptor antagonist that achieves therapeutic effect and eliminates rapidly. Its antiplatelet activity is unaffected by stagnation of blood, nor is it influenced by patient's sex, age, renal status, or hepatic function. Our institutional alternative intraoperative anticoagulation strategy for HIT patients is to administer cangrelor with a loading dose of 30 μg/kg, followed by continuous infusion of 4 μg/kg/min throughout CPB via a dedicated intravenous access. VerifyNow P2Y12 reaction unit point-of-care assay is utilized to monitor platelet inhibition throughout surgery. Cangrelor infusion is discontinued 10 minutes prior to heparin reversal with protamine. Ten urgent/emergent cardiovascular surgeries were performed at our institution using cangrelor with heparin for anticoagulation during CPB, and the majority were pulmonary thromboendarterectomy (60%). HIT was confirmed in 3 cases and was suspected in 4 which was found to be negative after the operation. One case of subacute B HIT and 2 cases of remote HIT were included in this series. This novel alternative intraoperative anticoagulation strategy was well tolerated by all patients. There was neither serious postoperative thrombotic event nor major postoperative bleeding complication that required reoperation. One death occurred in a patient with advanced intracardiac malignancy, whose life support was ultimately withdrawn postoperatively. Median postoperative intensive care unit stay was 7.2 ± 5.5 days, while median postoperative hospital stay was 16.3 ± 10.8 days. In patients with various phases of HIT who require urgent/emergent on-pump cardiovascular surgery, the use of cangrelor with heparin may be a convenient, safe, and effective alternative intraoperative anticoagulation strategy providing acceptable outcomes.
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http://dx.doi.org/10.1053/j.semtcvs.2019.10.002DOI Listing
March 2021

Ramelteon for Prevention of Postoperative Delirium: A Randomized Controlled Trial in Patients Undergoing Elective Pulmonary Thromboendarterectomy.

Crit Care Med 2019 12;47(12):1751-1758

Division of Pulmonary, Critical Care and Sleep Medicine, University of California San Diego School of Medicine, La Jolla, CA.

Objectives: To assess the efficacy of ramelteon in preventing delirium, an acute neuropsychiatric condition associated with increased morbidity and mortality, in the perioperative, ICU setting.

Design: Parallel-arm, randomized, double-blinded, placebo-controlled trial.

Setting: Academic medical center in La Jolla, California.

Patients: Patients greater than or equal to 18 years undergoing elective pulmonary thromboendarterectomy.

Interventions: Ramelteon 8 mg or matching placebo starting the night prior to surgery and for a maximum of six nights while in the ICU.

Measurements And Main Results: Incident delirium was measured twice daily using the Confusion Assessment Method-ICU. The safety outcome was coma-free days assessed by the Richmond Agitation-Sedation Scale. One-hundred twenty participants were enrolled and analysis completed in 117. Delirium occurred in 22 of 58 patients allocated to placebo versus 19 of 59 allocated to ramelteon (relative risk, 0.8; 95% CI, 0.5-1.4; p = 0.516). Delirium duration, as assessed by the number of delirium-free days was also similar in both groups (placebo median 2 d [interquartile range, 2-3 d] vs ramelteon 3 d [2-5 d]; p = 0.181). Coma-free days was also similar between groups (placebo median 2 d [interquartile range, 1-3 d] vs ramelteon 3 d [2-4 d]; p = 0.210). We found no difference in ICU length of stay (median 4 d [interquartile range, 3-5 d] vs 4 d [3-6 d]; p = 0.349), or in-hospital mortality (four vs three deaths; relative risk ratio, 0.7; 95% CI, 0.2-3.2; p = 0.717), all placebo versus ramelteon, respectively.

Conclusions: Ramelteon 8 mg did not prevent postoperative delirium in patients admitted for elective cardiac surgery.
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http://dx.doi.org/10.1097/CCM.0000000000004004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861685PMC
December 2019

Prior Sternotomy in Transvenous Lead Extraction: Risk Analysis Tempered by Clinical Experience.

Circ Arrhythm Electrophysiol 2019 09 16;12(9):e007762. Epub 2019 Sep 16.

Department of Electrophysiology, University of California, San Diego Health System, Sulpizio Cardiovascular Center, San Diego, CA.

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http://dx.doi.org/10.1161/CIRCEP.119.007762DOI Listing
September 2019

Outcomes of heart transplantation from hepatitis C virus-positive donors.

J Heart Lung Transplant 2019 12 24;38(12):1259-1267. Epub 2019 Aug 24.

Division of Cardiovascular Medicine, Department of Medicine, University of California, San Diego, San Diego, California, USA.

Background: National data demonstrate that increasing opportunities exist for organ donation among hepatitis C virus (HCV)-infected individuals.

Methods: We developed a clinical practice protocol for the acceptance of HCV+ organs for HCV- patients who underwent heart transplantation (HT) and retrospectively reviewed the outcomes at our institution. Inclusion criteria were as follows: all adult patients listed for HT. Exclusion criteria were as follows: pre-existing HIV or active hepatitis B viremia in the recipient/donor.

Results: We transplanted 21 patients from HCV+ donors. Nineteen were viremic donors, and 2 were non-viremic donors. The recipients included 18 patients who underwent HT alone, and 3 patients who underwent combined heart-kidney transplants. There was no HCV transmission from the non-viremic donors (n = 2). All 19 recipients of the viremic donors developed HCV infection (100% transmission). The median age of the viremic donors was 34 years (interquartile range 30-46), and 84.2% were considered US Public Health Service-increased risk. Induction immunosuppression consisted of anti-thymocyte globulin (7/21), basiliximab (7/21), or none (8/21). Maintenance immunosuppression comprised tacrolimus, mycophenolate mofetil, and prednisone. Post-operative Week 2 HCV viral load was not related to induction. Direct anti-viral agent (DAA) therapy for a 12-week course consisted of glecaprevir/pibrentasvir (14/19, 74%), sofosbuvir/velpatasvir (2/19, 11%), elbasvir/grazoprevir (2/19, 11%), and ledipasvir/sofosbuvir (1/19, 5%). All the patients on DAA therapy cleared viremia. The sustained virological response rate at 12 weeks in 18 evaluable patients was 100%.

Conclusions: We report successful single-center experience using HCV+ organs for HT into HCV- recipients. We believe that there is utility in using such organs to expand the current donor pool. Further long-term follow-up is needed.
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http://dx.doi.org/10.1016/j.healun.2019.08.019DOI Listing
December 2019

The impact of using hepatitis c virus nucleic acid test-positive donor hearts on heart transplant waitlist time and transplant rate.

J Heart Lung Transplant 2019 11 14;38(11):1178-1188. Epub 2019 Aug 14.

Division of Cardiovascular and Thoracic Surgery, Department of Surgery, University of California, San Diego, La Jolla, California.

Background: Previous studies suggest that direct-acting anti-virals (DAAs) for the treatment of hepatitis C virus (HCV) infection permits the transplantation of HCV-viremic donor organs in uninfected recipients. This opportunity may expand the donor pool. We assessed the impact of using HCV nucleic acid test-positive (NAT+) donor hearts on heart transplant (HTx) waitlist time and transplant rate.

Methods: We retrospectively analyzed 156 patients who were listed for HTx from October 2015 through October 2018. Patients were stratified into 2 periods centered on April 27, 2017, when the protocol to accept HCV NAT+ donor organs for transplantation in non-HCV-infected recipients began, Period 1 (October 27, 2015 to April 26, 2017) and Period 2 (April 27, 2017 to October 26, 2018).

Results: In Period 1, 57 of the 71 patients on the HTx waitlist were transplanted, whereas in Period 2, 57 of the 85 patients were transplanted. The median waitlist time to transplant decreased from 63.1 days in Period 1 to 34.1 days in Period 2 (p = 0.002). The transplant rate increased from 168.2 per 100 patient-years in Period 1 to 280.0 per 100 patient-years in Period 2 (incidence rate ratio 2.0, 95% CI 1.2-3.3; p = 0.006). Waitlist mortality rate, hospital stay post-transplantation, and post-transplant mortality did not differ significantly between the time periods. Nineteen patients received HCV NAT+ donor hearts. The short-term post-transplant outcomes were similar between the recipients who received HCV NAT+ and HCV NAT- donor hearts.

Conclusions: This single-center retrospective analysis suggests that the use of HCV NAT+ donor hearts may result in a reduced HTx waitlist time and an increased transplant rate. In addition, transplanting HCV NAT+ donor hearts into non-HCV-infected recipients, followed by DAAs, can provide acceptable short-term post-transplant outcomes.
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http://dx.doi.org/10.1016/j.healun.2019.08.010DOI Listing
November 2019

Prevalence and Short-Term Clinical Outcome of Mobile Thrombi Detected on Transvenous Leads in Patients Undergoing Lead Extraction.

JACC Clin Electrophysiol 2019 06 27;5(6):657-664. Epub 2019 Feb 27.

Department of Medicine, Division of Cardiac Electrophysiology, University of California-San Diego, La Jolla, California.

Objectives: This study sought to prospectively evaluate the prevalence, risk factors, and short-term major clinical outcomes of mobile thrombus detected on transvenous leads in patients undergoing lead extraction.

Background: The prevalence and clinical significance of thrombus on transvenous leads in patients undergoing lead extraction is not well characterized.

Methods: Consecutive patients undergoing transvenous lead extraction for noninfectious indications were enrolled. Preoperative transesophageal echocardiograms were performed prospectively for all patients to examine for mobile thrombus. Anticoagulation was not started for thrombus unless other indications were present. Clinical endpoints of mortality and cardiovascular morbidity (symptomatic pulmonary embolism, myocardial infarction, or cerebrovascular accident) were assessed at a minimum of 2-month follow-up.

Results: A total of 108 patients underwent lead extraction for noninfectious indications. Lead thrombi were detected in 20 (18.5%) patients and all were <2 cm. Clinical and lead characteristics were not associated with formation of lead thrombi, except for younger patient age. In patients with detected thrombi, there were no short-term deaths, symptomatic pulmonary embolisms, or myocardial infarctions, except 1 patient with a stroke 3 months after lead extraction (7% vs. 5%; p = 1.00). Median follow-up was 9 months.

Conclusions: Mobile thrombi on transvenous leads are commonly found in patients referred for transvenous lead extraction and are rarely associated with acute major adverse outcomes. Careful extraction of leads with small incidentally detected thrombi can likely be performed without major acute clinical sequelae. Larger studies with longer follow-up are needed to further assess the long-term clinical significance of lead thrombi.
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http://dx.doi.org/10.1016/j.jacep.2019.01.007DOI Listing
June 2019

Benefits of Neurohormonal Therapy in Patients With Continuous-Flow Left Ventricular Assist Devices.

ASAIO J 2020 04;66(4):409-414

Aurora Cardiovascular Services, Aurora Sinai/Aurora St. Luke's Medical Centers, Milwaukee, Wisconsin.

Left ventricular assist devices (LVADs) have dramatically improved short-term outcomes among patients with advanced heart failure. While neurohormonal blockade (NHB) is the cornerstone of treatment for patients with heart failure with reduced ejection fraction, its effect after LVAD placement has not been established. We reviewed medical records of 307 patients who underwent primary LVAD implantation from January 2006 to September 2015 at two institutions in the United States. Patients were followed for at least 2 years post-LVAD implantation or until explantation, heart transplantation, or death. Cox regression analysis stratifying on center was used to assess associations with mortality. Neurohormonal blockade use was treated as a time-dependent predictor. Stepwise selection indicated treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEIs/ARBs) (hazard ratio [HR] = 0.53 [0.30-0.95], p = 0.03), age at the time of implantation (HR = 1.28 [1.05-1.56] per decade, p = 0.02), length of stay postimplantation (HR = 1.16 [1.11-1.21] per week, p < 0.01) and INTERMACS profile of 1 or 2 (HR = 1.86 [1.17-2.97], p < 0.01) were independent predictors of mortality. In this large, retrospective study, treatment with ACEIs or ARBs was an independent factor associated with decreased mortality post-LVAD placement.
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http://dx.doi.org/10.1097/MAT.0000000000001022DOI Listing
April 2020

Evaluation of a lateral thoracotomy implant approach for a centrifugal-flow left ventricular assist device: The LATERAL clinical trial.

J Heart Lung Transplant 2019 04;38(4):344-351

Division of Cardiothoracic Surgery, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.

Background: The HeartWare centrifugal-flow ventricular assist device system (HVAD) is a viable option for treatment of advanced heart failure. There is a growing trend toward the use of less invasive techniques in cardiac surgery, and the thoracotomy technique for HVAD implantation may provide benefits not available with conventional approaches.

Methods: The LATERAL trial is a multicenter, prospective, non-randomized, single-arm trial that utilized data from 144 patients enrolled in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database at 26 centers in the United States and Canada. The primary composite end-point was success at 180 days defined as alive on the originally implanted device and free from disabling stroke (modified Rankin Scale score >3), transplanted or explanted for recovery. The key secondary end-point was mean length of initial hospital stay.

Results: The primary end-point was successfully achieved in 88.1% of patients and was significantly greater than the pre-defined performance goal of 77.5% set from historical sternotomy data (p = 0.0012). The key secondary end-point-mean length of initial hospital stay -was 18 days and was significantly shorter than the pre-defined performance goal of 26.1 days obtained from historical sternotomy data (p < 0.0001). The adverse event profile further demonstrated the safety of the thoracotomy approach. The overall patient survival was good, and bleeding requiring reoperation was significantly less frequent than that observed in previous studies using the sternotomy approach.

Conclusions: This prospective clinical trial provides validation that implantation of the HVAD system via the thoracotomy approach used in the LATERAL study represents a safe and effective alternative to median sternotomy in selected patients intended for a bridge-to-transplant indication.
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http://dx.doi.org/10.1016/j.healun.2019.02.002DOI Listing
April 2019