Publications by authors named "Samuel Kim"

265 Publications

Center Volume Impacts Readmissions and Mortality Following Congenital Cardiac Surgery.

J Pediatr 2021 Sep 18. Epub 2021 Sep 18.

Cardiovascular Outcomes Research Laboratories (CORELAB), David Geffen School of Medicine at UCLA; Division of Cardiac Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA. Electronic address:

Objective: To characterize the relationship between surgical volume and postoperative outcomes in congenital heart surgery, we used a national cohort to assess costs, readmissions and complications in children undergoing cardiac operations.

Study Design: The Nationwide Readmissions Database was used to identify pediatric patients (≤18 years) undergoing congenital cardiac surgery from 2010-2017. Hospitals were categorized based on deciles and tertiles of annual caseload with high-volume categorized as the highest tertile of volume. Multivariable regression models adjusting for patient and hospital characteristics were utilized to study the impact of volume on 30-day non-elective readmission, mortality, home discharge and resource utilization.

Results: Of an estimated 69,448 hospitalizations included for analysis, 56,672 (82%) occurred at high volume centers. After adjustment for key clinical factors, each decile increase in volume was associated with 25% relative reduction in odds of mortality, 14% reduction in odds of non-home discharge and 4% relative reduction in likelihood of 30-day non-elective readmission. After risk adjustment, each incremental increase in volume decile was associated with a half-day reduction in hospital length of stay but did not alter costs of the index hospitalization. However, after including all readmissions within 30-days of the index discharge, high volume centers were associated with significantly lower costs compared with low volume hospitals.

Conclusions: Increased congenital cardiac surgery volume is associated with improved mortality, reduced duration of hospitalization, 30-day readmissions and resource use. These findings demonstrate the inverse relationship between hospital volume and resource use and may have implications for centralization of care for congenital cardiac surgery.
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http://dx.doi.org/10.1016/j.jpeds.2021.09.017DOI Listing
September 2021

Association of Donor Hypertension and Outcomes in Orthotopic Heart Transplantation.

Clin Transplant 2021 Sep 13:e14484. Epub 2021 Sep 13.

Cardiovascular Outcomes Research Laboratories, David Geffen School of Medicine University of California, Los Angeles, CA, USA.

The present study examined the impact of donor hypertension on recipient survival and offer acceptance practices in the United States. This was a retrospective study of all patients undergoing OHT from 1995 to 2019 using the United Network for Organ Sharing and Potential Transplant Recipient file databases. Hypertensive donors were stratified by Short (0-5 years) and Prolonged (>5 years) hypertension. Multivariable logistic regression was used to analyze offer acceptance practices while Cox proportional-hazards models were used to compare mortality across groups. Of 38,338 heart transplants meeting study criteria, 5,662 were procured from hypertensive donors (69% Short and 31% Prolonged). After adjustment, Prolonged donor hypertension was associated with increased mortality (hazard ratio, HR, 1.31, 95% confidence interval, CI, 1.04-1.64), while recipients of Short donors experienced no decrement in post-transplant survival. Both Short and Prolonged hypertension were independently associated with decreased odds of offer acceptance (odds ratio, OR 0.92 95%CI:0.88-0.96 and OR 0.93 95%CI: 0.88-0.99, respectively). While prolonged untreated hypertension in OHT donors is associated with a slight decrement in recipient survival, donors with ≤5 years of hypertension yielded similar outcomes. Donor hypertension was associated with reduced organ offer acceptance, highlighting a potential source of organ underutilization. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/ctr.14484DOI Listing
September 2021

Perspective on reducing errors in research.

Contemp Clin Trials Commun 2021 Sep 18;23:100838. Epub 2021 Aug 18.

Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.

Efforts to ensure research integrity has mostly focused on research misconduct. However, the complexity of research operations and processes makes research work also prone to unintentional errors. To safeguard against errors and their consequences, strategies for error reduction, detection, and mitigation can be applied to research work. Nurturing a scientific culture that encourages error disclosure and rectification is essential to reduce the negative consequences of errors. Creating repositories where errors can be reported can enable learning from errors and creation of more robust research processes.
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http://dx.doi.org/10.1016/j.conctc.2021.100838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390521PMC
September 2021

Continued Relevance of Minimum Volume Standards for Elective Esophagectomy: A National Perspective.

Ann Thorac Surg 2021 Aug 23. Epub 2021 Aug 23.

Cardiovascular Outcomes Research Laboratories (CORELAB), David Geffen School of Medicine at UCLA. Electronic address:

Background: Despite minimum volume recommendations, the majority of esophagectomies are performed at centers with fewer than 20 annual cases. The present study examined the impact of institutional esophagectomy volume on in-hospital mortality, complications and resource use following esophageal resection.

Methods: The 2010-2018 Nationwide Readmissions Database was queried to identify all adult patients undergoing esophagectomy for malignancy. Hospitals were categorized as high-volume (HVH) if performing at least 20 esophagectomies annually, and low-volume (LVH) if fewer. Multivariable models were developed to study the impact of volume on outcomes of interest which included in-hospital mortality, complications, duration of hospitalization (LOS), inflation adjusted costs, readmissions, and non-home discharge.

Results: Of an estimated 23,176 hospitalizations, 45.6% occurred at HVH. Incidence of esophagectomy increased significantly along with median institutional case load over the study period, while the proportion on hospitals considered HVH remained steady at approximately 7.4%. After adjusting for relevant patient and hospital characteristics, HVH was associated with decreased mortality (AOR=0.65), LOS (β=-1.83 days), pneumonia (AOR=0.69), prolonged ventilation (AOR=0.50), sepsis (AOR=0.80), and tracheostomy (AOR=0.66), but increased odds of non-home discharge (AOR=1.56, all P<0.01), with LVH as reference.

Conclusions: Many clinical outcomes of esophagectomy are improved with no increment in costs when performed at centers with an annual caseload of at least 20, as recommended by patient advocacy organizations. These findings suggest that centralization of esophageal resections to high-volume centers may be congruent with value-based care models.
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http://dx.doi.org/10.1016/j.athoracsur.2021.07.061DOI Listing
August 2021

Lung donation following SARS-CoV-2 infection.

Am J Transplant 2021 Jul 31. Epub 2021 Jul 31.

Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

There have been over 177 million cases of COVID-19 worldwide, many of whom could be organ donors. Concomitantly, there is an anticipated increase in the need for donor lungs due to expanding indications. Given that the respiratory tract is most commonly affected by COVID-19, there is an urgent need to develop donor assessment criteria while demonstrating safety and "efficacy" of lung donation following COVID-19 infection. Accordingly, we report an intentional transplant using lungs from a donor with recent, microbiologically confirmed, COVID-19 infection into a recipient suffering from COVID-19 induced ARDS and pulmonary fibrosis. In addition to the standard clinical assays, both donor and recipient lungs were analyzed using RNAscope, which confirmed that tissues were negative for SARS-CoV-2. Immunohistochemistry demonstrated colocalized KRT17+ basaloid-like epithelium and COL1A1+ fibroblasts, a marker suggestive of lung fibrosis in COVID-19 associated lung disease, in the explanted recipient lungs but absent in the donor lungs. We demonstrate that following a thorough assessment, lung donation following resolved COVID-19 infection is safe and feasible.
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http://dx.doi.org/10.1111/ajt.16777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441925PMC
July 2021

Repair of Isolated Native Mitral Valve Endocarditis: A Propensity Matched Study.

Semin Thorac Cardiovasc Surg 2021 Jun 29. Epub 2021 Jun 29.

Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.. Electronic address:

In the setting of chronic primary mitral regurgitation, the benefit of mitral valve repair over replacement is well established. However, data comparing outcomes for mitral valve surgery for endocarditis is limited. We sought to determine whether mitral valve repair offers traditional advantages over replacement in the endocarditis population. Retrospective review of our institutional mitral valve database (N = 8,181) was performed between 1998 and 2019 for all adult patients undergoing isolated mitral valve surgery for endocarditis. Patients were stratified by mitral valve repair or replacement and propensity score matching was performed to adjust for differences in baseline characteristics and degree of valve damage. Overall, 267 surgeries (124 repair, 153 replacement) met inclusion criteria during the study period. Following propensity matching, the repair cohort was associated with shorter initial ventilator times (5.6 vs 7.9 hours, p = 0.05), shorter ICU (28 vs 52 hours, p = 0.03), and hospital lengths of stays (7 vs 11 days, p < 0.01). Thirty-day mortality (0% vs 2.1%, p = 0.01) and 10-year survival (88% vs 86%, p = 0.55) were similar between cohorts. Patients in the repair cohort were less likely to require repeat mitral valve intervention at our institution for recurrent endocarditis than those in the replacement cohort (0% vs 10.6%, p = 0.03). Mitral valve repair is safe, when feasible, in the setting of isolated native valve endocarditis and may provide patients faster recovery. Experienced mitral surgeons should approach this patient population with a "repair if feasible" methodology.
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http://dx.doi.org/10.1053/j.semtcvs.2021.05.025DOI Listing
June 2021

Unhealthy Lifestyle and Gut Dysbiosis: A Better Understanding of the Effects of Poor Diet and Nicotine on the Intestinal Microbiome.

Front Endocrinol (Lausanne) 2021 8;12:667066. Epub 2021 Jun 8.

Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, United States.

The study of the intestinal or gut microbiome is a newer field that is rapidly gaining attention. Bidirectional communication between gut microbes and the host can impact numerous biological systems regulating immunity and metabolism to either promote or negatively impact the host's health. Habitual routines, dietary choices, socioeconomic status, education, host genetics, medical care and environmental factors can all contribute to the composition of an individual's microbiome. A key environmental factor that may cause negative outcomes is the consumption of nicotine products. The effects of nicotine on the host can be exacerbated by poor dietary choices and together can impact the composition of the gut microbiota to promote the development of metabolic disease including non-alcoholic fatty liver disease. This review explores the contribution of nicotine, poor dietary choices and other unhealthy lifestyle factors to gut dysbiosis.
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http://dx.doi.org/10.3389/fendo.2021.667066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218903PMC
June 2021

The 2018 adult heart allocation policy change benefits low-volume transplant centers.

Clin Transplant 2021 Jun 21. Epub 2021 Jun 21.

Cardiovascular Outcomes Research Laboratories (CORELAB), Division of Cardiac Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

Introduction: The effect of the 2018 adult heart allocation policy change at an institution-level remains unclear. The present study assessed the impact of the policy change by transplant center volume.

Methods: The United Network for Organ Sharing database was queried for all adults undergoing isolated heart transplantation from November 2016 to September 2020. Era 1 was defined as the period before the policy change and Era 2 afterwards. Hospitals were divided into low-(LVC) medium-(MVC) and high-volume (HVC) tertiles based on annual transplant center volume. Competing-risks regressions were used to determine changes in waitlist death/deterioration, while post-transplant mortality was assessed using multivariable Cox proportional-hazards models.

Results: A total of 3531 (47.0%) patients underwent heart transplantation in Era 1 and 3988 (53.0%) in Era 2. At LVC, Era 2 patients were less likely to experience death/deterioration on the waitlist (subhazard ratio .74, 95% CI .63-.88), while MVC and HVC patients experienced similar waitlist death/deterioration across eras. After adjustment, transplantation in Era 2 was associated with worse 1-year mortality at MVC (hazard ratio, HR, 1.42 95% CI 1.02-1.96) and HVC (HR 1.42, 95% CI 1.02-1.98) but not at LVC.

Conclusion: Early analysis shows that LVC may be benefitting under the new allocation scheme.
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http://dx.doi.org/10.1111/ctr.14389DOI Listing
June 2021

Assessing predicted heart mass size matching in obese heart transplant recipients.

J Heart Lung Transplant 2021 Aug 12;40(8):805-813. Epub 2021 May 12.

Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Background: Predicted heart mass (PHM) is currently the most reliable metric for donor-recipient size matching in heart transplantation. Undersizing PHM donor-recipient match more than 20% independently predicts reduced survival. However, it is unclear if this is the case in obese recipients, in whom size matching can be challenging. We examined the use of PHM undersized hearts in obese recipients and assessed its impact on survival.

Methods: The United Network for Organ Sharing database was queried for adult patients undergoing heart transplantation from 1995 to 2020. Obese recipients (BMI ≥ 30) were categorized based on donor-recipient PHM match ≤-20% (undersized) or >-20% (size-matched). Nearest-neighbor propensity score matching was performed to adjust for baseline differences between cohorts. Temporal outcomes were compared by Kaplan-Meier survival analysis.

Results: A total of 13,668 obese recipients met inclusion criteria, with 9.6% receiving undersized and 90.4% receiving size-matched hearts. The proportion of undersized donor hearts in obese recipients significantly decreased over the study period (16.2% [1995] to 7.4% [2019], NP-trend < 0.001). Propensity-score matching resulted in 984 well-matched pairs of undersized and size-matched obese recipients. Recipients of undersized hearts saw similar 30-day mortality (5.5% vs 6.0%, p= 0.11) and re-transplantation rates (1.2% vs 1.2%, p = 1.00) as size-matched recipients. Survival at 1 year (88.4% vs 87.9%, p = 0.14), and 15 years (35.1% vs 31.0%, p = 0.12) was similar across cohorts.

Conclusions: A decreasing proportion of PHM undersized hearts are being utilized in obese recipients. However, utilizing PHM undersized hearts in obese recipients was not associated with a detriment in survival.
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http://dx.doi.org/10.1016/j.healun.2021.04.020DOI Listing
August 2021

Thermal Transport across Metal/β-GaO Interfaces.

ACS Appl Mater Interfaces 2021 Jun 10;13(24):29083-29091. Epub 2021 Jun 10.

George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, United States.

In this work, we study the thermal transport at β-GaO/metal interfaces, which play important roles in heat dissipation and as electrical contacts in β-GaO devices. A theoretical Landauer approach was used to model and elucidate the factors that impact the thermal transport at these interfaces. Experimental measurements using time-domain thermoreflectance (TDTR) provided data for the thermal boundary conductance (TBC) between β-GaO and a range of metals used to create both Schottky and ohmic electrical contacts. From the modeling and experiments, the relation between the metal cutoff frequency and the corresponding TBC is observed. Moreover, the effect of the metal cutoff frequency on TBC is seen as the most significant factor followed by chemical reactions and defects between the metal and the β-GaO. Among all β-GaO/metal interfaces, for Schottky contacts, Ni/β-GaO interfaces show the highest TBC, while for ohmic contacts, Cr/β-GaO interfaces show the highest TBC. While there is a clear correlation between TBC and the phonon cutoff frequency of metal contacts, it is also important to control the chemical reactions and other defects at interfaces to maximize the TBC in this system.
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http://dx.doi.org/10.1021/acsami.1c05191DOI Listing
June 2021

Case Report: Identification of a Microdeletion 1q44 in a Patient With Seizures and Developmental Delay.

Front Genet 2021 20;12:648351. Epub 2021 May 20.

Department of Neurology, Children's Hospital of Nanjing Medical University, Nanjing, China.

1q44 microdeletion syndrome is difficult to diagnose due to the wide phenotypic spectrum and strong genetic heterogeneity. We explore the correlation between the chromosome microdeletions and phenotype in a child with 1q44 microdeletion syndrome, we collected the clinical features of the patient and combined them with adjacent copy number variation (CNV) regions previously reported. We collected the full medical history of the patient and summarized her clinical symptoms. Whole-exome sequencing (WES) and CapCNV analysis were performed with DNA extracted from both the patient's and her parents' peripheral blood samples. Fluorescent quantitative PCR (q-PCR) was performed for the use of verification to the CNV regions. A 28.7 KB microdeletion was detected in the 1q44 region by whole-exome sequencing and low-depth whole-genome sequencing. The deleted region included the genes COX20 and HNRNPU. As verification, karyotype analysis showed no abnormality, and the results of qPCR were consistent with that of whole-exome sequencing and CapCNV analysis. The patient was diagnosed with 1q44 microdeletion syndrome with clinical and genetic analysis. Analyzing both whole-exome sequencing and CapCNV analysis can not only improve the diagnostic rate of clinically suspected syndromes that present with intellectual disability (ID) and multiple malformations but also support further study of the correlation between CNVs and clinical phenotypes. This study lays the foundation for the further study of the pathogenesis of complex diseases.
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http://dx.doi.org/10.3389/fgene.2021.648351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173053PMC
May 2021

Operative Versus Nonoperative Management of Acute Pediatric Monteggia Injuries With Complete Ulna Fractures.

J Pediatr Orthop 2021 Jun 2. Epub 2021 Jun 2.

UCLA Orthopaedic Hospital Department of Orthopaedics, David Geffen School of Medicine, University of California, Los Angeles UCLA David Geffen School of Medicine, University of California, Los Angeles Orthopaedic Institute for Children, Los Angeles, CA The Children's Hospital of Philadelphia, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA.

Background: The treatment of acute pediatric Monteggia injuries involving a complete fracture of the ulna remains controversial. The purpose of this study is to compare the outcomes of immediate operative fixation to a trial of closed reduction and casting of acute pediatric Monteggia fractures involving complete ulna fractures.

Methods: We performed a retrospective analysis of 73 patients with Monteggia injuries with complete ulna fractures presenting to 2 pediatric trauma centers from 2008 to 2018. Patients were divided in 2 groups based on the treatment received: patients in group 1 (n=37, 51%) received surgical treatment; patients in group 2 (n=36, 49%) received a trial of closed reduction and casting. The mean follow-up of 15.2 weeks (range, 4.1 to 159 wk). The incidence of radiocapitellar joint redislocation, need for further intervention, complications, and recovery of range of motion was compared between the groups.

Results: There were no significant differences between groups 1 and 2 with regards to age (6 vs. 5.8 y, P=0.69), sex (54% vs. 47% female, P=0.64), or the mean maximal ulnar angulation (23 vs. 19 degrees, P=0.94). There was a higher proportion of proximal ulna fractures in group 1 versus 2 (62% vs. 33%, respectively, P=0.02). Bado type III and IV fractures were associated with operative management [odds ratio=22 (95% confidence interval: 1.68-288.7) and 14.9 (95% confidence interval: 2.09-106), respectively]. In group 2, 5 patients (13.9%) sustained a loss of radiocapitellar joint reduction following closed reduction and casting and ultimately received operative treatment. At final follow-up, there were no cases of recurrent radiocapitellar dislocation in either group, all patients achieved fracture union and regained full elbow range of motion.

Conclusions: Even in the presence of a complete ulna fracture, a trial of nonoperative management of acute pediatric Monteggia fractures with closed reduction and casting can result in comparable outcomes to those obtained with immediate surgical management. The nonoperative management of Monteggia fractures requires close clinical follow-up to ensure no loss of reduction.

Level Of Evidence: Level IV-therapeutic studies, case series.
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http://dx.doi.org/10.1097/BPO.0000000000001868DOI Listing
June 2021

The Characterization of Postoperative Mechanical Respiratory Requirement in Neonates and Infants Undergoing Cardiac Surgery on Cardiopulmonary Bypass in a Single Tertiary Institution.

J Cardiothorac Vasc Anesth 2021 Apr 25. Epub 2021 Apr 25.

Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA; Department of Immunology, Harvard Medical School, Boston, MA. Electronic address:

Objectives: Although neonates and infants undergoing cardiac surgery on cardiopulmonary bypass (CPB) are at high risk of developing perioperative morbidity and mortality, including lung injury, the intraoperative profile of lung injury in this cohort is not well-described. Given that the postoperative course of patients in the pediatric cardiac surgical arena has become increasingly expedited, the objective of this study was to characterize the profiles of postoperative mechanical ventilatory support in neonates and infants undergoing cardiac surgery on CPB and to examine the characteristics of lung mechanics and lung injury in this patient population who are potentially amendable to early postoperative recovery in a single tertiary pediatric institution.

Design: A retrospective data analysis of neonates and infants who underwent cardiac surgery on cardiopulmonary bypass.

Setting: A single-center, university teaching hospital.

Participants: The study included 328 neonates and infants who underwent cardiac surgery on cardiopulmonary bypass.

Interventions: A subset of 128 patients were studied: 58 patients undergoing ventricular septal defect (VSD) repair, 36 patients undergoing complete atrioventricular canal (CAVC) repair, and 34 patients undergoing bidirectional Glenn (BDG) shunt surgery.

Measurements And Main Results: Of the entire cohort, 3.7% experienced in-hospital mortality. Among all surgical procedures, VSD repair (17.7%) was the most common, followed by CAVC repair (11.0%) and BDG shunt surgery (10.4%). Of patients who underwent VSD repair, CAVC repair, and BDG shunt surgery, 65.5%, 41.7%, and 67.6% were off mechanical ventilatory support within 24 hours postoperatively, respectively. In all three of the surgical repairs, lung compliance decreased after CPB compared to pre-CPB phase. Sixty point three percent of patients with VSD repair and 77.8% of patients with CAVC repair showed a PaO/FO (P/F) ratio of <300 after CPB. Post- CPB P/F ratios of 120 for VSD patients and 100 for CAVC patients were considered as optimal cutoff values to highly predict prolonged (>24 hours) postoperative mechanical ventilatory support. A higher volume of transfused platelets also was associated with postoperative ventilatory support ≥24 hours in patients undergoing VSD repair, CAVC repair, and BDG shunt surgery.

Conclusions: There was a high incidence of lung injury after CPB in neonates and infants, even in surgeries amendable for early recovery. Given that CPB-related factors (CPB duration, crossclamp time) and volume of transfused platelet were significantly associated with prolonged postoperative ventilatory support, the underlying cause of cardiac surgery-related lung injury can be multi-factorial.
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http://dx.doi.org/10.1053/j.jvca.2021.04.023DOI Listing
April 2021

The Dietary Approaches to Stop Hypertension (DASH) Diet Pattern and Incident Heart Failure.

J Card Fail 2021 May;27(5):512-521

Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama.

Background: The Dietary Approaches to Stop Hypertension (DASH) diet pattern has shown some promise for preventing heart failure (HF), but studies have been conflicting.

Objective: To determine whether the DASH diet pattern was associated with incident HF in a large biracial and geographically diverse population.

Methods And Results: Among participants in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort study of adults aged ≥45 years who were free of suspected HF at baseline in 2003-2007, the DASH diet score was derived from the baseline food frequency questionnaire. The main outcome was incident HF defined as the first adjudicated HF hospitalization or HF death through December 31, 2016. We estimated hazard ratios for the associations of DASH diet score quartiles with incident HF, and incident HF with reduced ejection fraction and HF with preserved ejection fraction using the Lunn-McNeil extension to the Cox model. We tested for several prespecified interactions, including with age. Compared with the lowest quartile, individuals in the second to fourth DASH diet score quartiles had a lower risk for incident HF after adjustment for sociodemographic and health characteristics: quartile 2 hazard ratio, 0.69 (95% confidence interval [CI], 0.56-0.85); quartile 3 hazard ratio, 0.71 (95% CI, 0.58-0.87); and quartile 4 hazard ratio, 0.73 (95% CI, 0.58-0.92). When stratifying results by age, quartiles 2-4 had a lower hazard for incident HF among those age <65 years, quartiles 3-4 had a lower hazard among those age 65-74, and the quartiles had similar hazard among those age ≥75 years (P = .003). We did not find a difference in the association of DASH diet with incident HF with reduced ejection fraction vs HF with preserved ejection fraction (P = .11).

Conclusions: DASH diet adherence was inversely associated with incident HF, specifically among individuals <75 years old.
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http://dx.doi.org/10.1016/j.cardfail.2021.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396128PMC
May 2021

Impact of frailty on acute outcomes of endovascular thoracic and abdominal aneurysm repair.

Surgery 2021 07 30;170(1):304-310. Epub 2021 Apr 30.

Cardiovascular Outcomes Research Laboratories (CORELAB), Division of Cardiac Surgery, Department of Surgery, University of California, Los Angeles, CA. Electronic address:

Background: While coding-based frailty tools may readily identify at-risk patients, they have not been adopted into screening guidelines for endovascular abdominal aortic aneurysm repair or thoracic endovascular aortic repair at the national level. We aimed to characterize the impact of frailty on clinical outcomes and resource use after endovascular aneurysm repair and thoracic endovascular aortic repair using a nationally representative cohort.

Methods: The 2005 to 2018 National Inpatient Sample was queried to identify all adults undergoing elective endovascular abdominal aortic aneurysm repair or thoracic endovascular aortic repair. Patients were considered "frail" if they suffered from any frailty-defining diagnoses in the Johns Hopkins Adjusted Clinical Groups. Multivariable regression models were used to identify independent associations with outcomes of interest including in-hospital mortality, nonhome discharge, and hospitalization costs.

Results: Of an estimated 301,869 patients, 273,415 (90.6%) underwent endovascular aneurysm repair and the remainder thoracic endovascular aortic repair. Frailty prevalence was lower in the endovascular aneurysm repair cohort (2.3%) compared with thoracic endovascular aortic repair (4.7%). After adjustment, frailty was associated with higher in-hospital mortality (endovascular aneurysm repair odds ratio 4.0; thoracic endovascular aortic repair odds ratio 2.5), nonhome discharge rates (endovascular aneurysm repair odds ratio 7.2; thoracic endovascular aortic repair odds ratio 4.2), and predicted costs (endovascular aneurysm repair ß coefficient +$10.6K; thoracic endovascular aortic repair ß coefficient +$38.2K) for both cohorts.

Conclusion: Given that frailty portends inferior outcomes for both endovascular aneurysm repair and thoracic endovascular aortic repair, its inclusion in existing risk models may better inform shared decision-making.
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http://dx.doi.org/10.1016/j.surg.2021.03.053DOI Listing
July 2021

Optimized polyepitope neoantigen DNA vaccines elicit neoantigen-specific immune responses in preclinical models and in clinical translation.

Genome Med 2021 04 21;13(1):56. Epub 2021 Apr 21.

Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO, 63110, USA.

Background: Preclinical studies and early clinical trials have shown that targeting cancer neoantigens is a promising approach towards the development of personalized cancer immunotherapies. DNA vaccines can be rapidly and efficiently manufactured and can integrate multiple neoantigens simultaneously. We therefore sought to optimize the design of polyepitope DNA vaccines and test optimized polyepitope neoantigen DNA vaccines in preclinical models and in clinical translation.

Methods: We developed and optimized a DNA vaccine platform to target multiple neoantigens. The polyepitope DNA vaccine platform was first optimized using model antigens in vitro and in vivo. We then identified neoantigens in preclinical breast cancer models through genome sequencing and in silico neoantigen prediction pipelines. Optimized polyepitope neoantigen DNA vaccines specific for the murine breast tumor E0771 and 4T1 were designed and their immunogenicity was tested in vivo. We also tested an optimized polyepitope neoantigen DNA vaccine in a patient with metastatic pancreatic neuroendocrine tumor.

Results: Our data support an optimized polyepitope neoantigen DNA vaccine design encoding long (≥20-mer) epitopes with a mutant form of ubiquitin (Ub) fused to the N-terminus for antigen processing and presentation. Optimized polyepitope neoantigen DNA vaccines were immunogenic and generated robust neoantigen-specific immune responses in mice. The magnitude of immune responses generated by optimized polyepitope neoantigen DNA vaccines was similar to that of synthetic long peptide vaccines specific for the same neoantigens. When combined with immune checkpoint blockade therapy, optimized polyepitope neoantigen DNA vaccines were capable of inducing antitumor immunity in preclinical models. Immune monitoring data suggest that optimized polyepitope neoantigen DNA vaccines are capable of inducing neoantigen-specific T cell responses in a patient with metastatic pancreatic neuroendocrine tumor.

Conclusions: We have developed and optimized a novel polyepitope neoantigen DNA vaccine platform that can target multiple neoantigens and induce antitumor immune responses in preclinical models and neoantigen-specific responses in clinical translation.
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http://dx.doi.org/10.1186/s13073-021-00872-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059244PMC
April 2021

Decreased 11β-Hydroxysteroid Dehydrogenase Type 2 Expression in the Kidney May Contribute to Nicotine/Smoking-Induced Blood Pressure Elevation in Mice.

Hypertension 2021 Jun 5;77(6):1940-1952. Epub 2021 Apr 5.

Department of Pediatrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, China (Y.W., R.Y., Y.L.).

[Figure: see text].
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119334PMC
June 2021

Early outcomes after lung transplantation for severe COVID-19: a series of the first consecutive cases from four countries.

Lancet Respir Med 2021 05 31;9(5):487-497. Epub 2021 Mar 31.

Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria.

Background: Lung transplantation is a life-saving treatment for patients with end-stage lung disease; however, it is infrequently considered for patients with acute respiratory distress syndrome (ARDS) attributable to infectious causes. We aimed to describe the course of disease and early post-transplantation outcomes in critically ill patients with COVID-19 who failed to show lung recovery despite optimal medical management and were deemed to be at imminent risk of dying due to pulmonary complications.

Methods: We established a multi-institutional case series that included the first consecutive transplants for severe COVID-19-associated ARDS known to us in the USA, Italy, Austria, and India. De-identified data from participating centres-including information relating to patient demographics and pre-COVID-19 characteristics, pretransplantation disease course, perioperative challenges, pathology of explanted lungs, and post-transplantation outcomes-were collected by Northwestern University (Chicago, IL, USA) and analysed.

Findings: Between May 1 and Sept 30, 2020, 12 patients with COVID-19-associated ARDS underwent bilateral lung transplantation at six high-volume transplant centres in the USA (eight recipients at three centres), Italy (two recipients at one centre), Austria (one recipient), and India (one recipient). The median age of recipients was 48 years (IQR 41-51); three of the 12 patients were female. Chest imaging before transplantation showed severe lung damage that did not improve despite prolonged mechanical ventilation and extracorporeal membrane oxygenation. The lung transplant procedure was technically challenging, with severe pleural adhesions, hilar lymphadenopathy, and increased intraoperative transfusion requirements. Pathology of the explanted lungs showed extensive, ongoing acute lung injury with features of lung fibrosis. There was no recurrence of SARS-CoV-2 in the allografts. All patients with COVID-19 could be weaned off extracorporeal support and showed short-term survival similar to that of transplant recipients without COVID-19.

Interpretation: The findings from our report show that lung transplantation is the only option for survival in some patients with severe, unresolving COVID-19-associated ARDS, and that the procedure can be done successfully, with good early post-transplantation outcomes, in carefully selected patients.

Funding: National Institutes of Health. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/S2213-2600(21)00077-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012035PMC
May 2021

Therapeutic Efficacy of Cryopreserved, Allogeneic Extracellular Vesicles for Treatment of Acute Myocardial Infarction.

Int Heart J 2021 Mar 17;62(2):381-389. Epub 2021 Mar 17.

Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania.

Extracellular vesicles (EV) that are derived from endothelial progenitor cells (EPC) have been determined to be a novel therapy for acute myocardial infarction, with a promise for immediate "off-the-shelf" delivery. Early experience suggests delivery of EVs from allogeneic sources is safe. Yet, clinical translation of this therapy requires assurances of both EV stability following cryopreservation and absence of an adverse immunologic response to EVs from allogeneic donors. Thus, more bioactivity studies on allogeneic EVs after cold storage are necessary to establish quality standards for its widespread clinical use. Thus, in this study, we aimed to demonstrate the safety and efficacy in delivering cryopreserved EVs in allogeneic recipients as a therapy for acute myocardial infarction.In this present study, we have analyzed the cardioprotective effects of allogeneic EPC-derived EVs after storage at -80°C for 2 months, using a shear-thinning gel (STG) as an in vivo delivery vehicle. EV size, proteome, and nucleic acid cargo were observed to remain steady through extended cryopreservation via nanoparticle tracking analysis, mass spectrometry, and nanodrop analysis, respectively. Fresh and previously frozen EVs in STG were delivered intramyocardially in a rat model of myocardial infarction (MI), with both showing improvements in contractility, angiogenesis, and scar thickness in comparison to phosphate-buffered saline (PBS) and STG controls at 4 weeks post-MI. Pathologic analyses and flow cytometry revealed minimal inflammatory and immune upregulation upon exposure of tissue to EVs pooled from allogeneic donor cells.Allogeneic EPC-EVs have been known to elicit minimal immune activity and retain therapeutic efficacy after at least 2 months of cryopreservation in a post-MI model.
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http://dx.doi.org/10.1536/ihj.20-224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103174PMC
March 2021

Tumor Burden and Immunotherapy: Impact on Immune Infiltration and Therapeutic Outcomes.

Front Immunol 2020 1;11:629722. Epub 2021 Feb 1.

Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.

Cancer immunotherapy has revolutionized the treatment landscape in medical oncology, but its efficacy has been variable across patients. Biomarkers to predict such differential response to immunotherapy include cytotoxic T lymphocyte infiltration, tumor mutational burden, and microsatellite instability. A growing number of studies also suggest that baseline tumor burden, or tumor size, predicts response to immunotherapy. In this review, we discuss the changes in immune profile and therapeutic responses that occur with increasing tumor size. We also overview therapeutic approaches to reduce tumor burden and favorably modulate the immune microenvironment of larger tumors.
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http://dx.doi.org/10.3389/fimmu.2020.629722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882695PMC
June 2021

Population-specific causal disease effect sizes in functionally important regions impacted by selection.

Nat Commun 2021 02 17;12(1):1098. Epub 2021 Feb 17.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Many diseases exhibit population-specific causal effect sizes with trans-ethnic genetic correlations significantly less than 1, limiting trans-ethnic polygenic risk prediction. We develop a new method, S-LDXR, for stratifying squared trans-ethnic genetic correlation across genomic annotations, and apply S-LDXR to genome-wide summary statistics for 31 diseases and complex traits in East Asians (average N = 90K) and Europeans (average N = 267K) with an average trans-ethnic genetic correlation of 0.85. We determine that squared trans-ethnic genetic correlation is 0.82× (s.e. 0.01) depleted in the top quintile of background selection statistic, implying more population-specific causal effect sizes. Accordingly, causal effect sizes are more population-specific in functionally important regions, including conserved and regulatory regions. In regions surrounding specifically expressed genes, causal effect sizes are most population-specific for skin and immune genes, and least population-specific for brain genes. Our results could potentially be explained by stronger gene-environment interaction at loci impacted by selection, particularly positive selection.
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http://dx.doi.org/10.1038/s41467-021-21286-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889654PMC
February 2021

Relationship of Cardiopulmonary Bypass Times and Outcomes in Minimally Invasive Mitral Valve Surgery.

Ann Thorac Surg 2021 09 23;112(3):1032-1033. Epub 2021 Jan 23.

Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, 3400 Spruce St, 6 Silverstein Pavilion, Philadelphia, PA 19104. Electronic address:

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http://dx.doi.org/10.1016/j.athoracsur.2021.01.019DOI Listing
September 2021

Prelamination of Vascularized Tensor Fascia Lata for Complex Abdominal Wall Reconstruction.

Ann Plast Surg 2021 03;86(3S Suppl 2):S332-S335

From the Division of Plastic Surgery, Department of Surgery.

Abstract: There are 2 to 5 million laparotomies performed in the United States annually. Of these, 250,000 to 350,000 will undergo a ventral hernia repair. Repairs are often complicated by recurrence and infection. These risks are significantly increased in previously infected repairs, with reported recurrence rates varying from 17% to 28% after repair of infected ventral hernias, double the rates reported for first-time uninfected repairs. We describe here a novel treatment strategy involving the creation then use of bilateral prelaminated permanent mesh-reinforced tensor fascia latae flaps for abdominal wall reconstruction in patients who have recurrent ventral hernias and had undergone previous repairs complicated by infection. Previous repairs included anterior components separation, thereby making subsequent fascial release techniques and achievement of a reinforced repair extremely unlikely. Three patients were treated by a single surgeon using this 2-stage technique. There have been no incidences of recurrence and no infections after 2 to 10 years. In these patients, the only conventional option would have been a bridged repair with absorbable mesh. Combining the advantages of permanent mesh and well-vascularized autologous tissue optimizes the repair's tensile strength while mitigating the chance of recurrent infection associated with the use of permanent mesh. We propose that this strategy may be an appropriate treatment option for patients with recurrent ventral hernias that have not responded to other conventional modalities of treatment.
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http://dx.doi.org/10.1097/SAP.0000000000002690DOI Listing
March 2021

Finding needles in a haystack: dissecting tumor heterogeneity with single-cell transcriptomic and chromatin accessibility profiling.

Curr Opin Genet Dev 2021 02 5;66:36-40. Epub 2021 Jan 5.

Genetics Department, Stanford University School of Medicine, Stanford, CA, United States. Electronic address:

Tumor evolution often results in a wealth of heterogeneous cancer cell types within a single tumor - heterogeneity that can include epigenetic and gene expression changes that are impossible to identify from histological features alone. The invasion of cancer cells into nearby healthy tissue, accompanied by the infiltration of responding immune cells, results in an even more complex architecture of tumor and non-tumor cells. However, bulk genomics-based methods can only assay the aggregate transcriptomic and epigenetic profiles across all of this rich cellular diversity. Such bulk averaging hides small subpopulations of tumor cells with unique phenotypes that might result in therapeutic resistance or metastatic progression. The advent of single-cell-based genomics assays for measuring transcription and chromatin accessibility - particularly scRNA-seq and scATAC-seq - has enabled the dissection of cell-types within tumors at a scale and resolution capable of unraveling the epigenetic and gene expression programs of rare and unique cellular subpopulations. This Review focuses on recent advances in scRNA-seq and scATAC-seq technologies and their application to cancer biology in the context of furthering our understanding of tumor heterogeneity.
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http://dx.doi.org/10.1016/j.gde.2020.11.008DOI Listing
February 2021

Impact of the Coronavirus Disease 2019 Pandemic on Utilization of Mechanical Circulatory Support As Bridge to Heart Transplantation.

ASAIO J 2021 04;67(4):382-384

From the Cardiovascular Outcomes Research Laboratories, Division of Cardiac Surgery, David Geffen School of Medicine University of California, Los Angeles, Los Angeles, California.

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http://dx.doi.org/10.1097/MAT.0000000000001387DOI Listing
April 2021

Comparative Effectiveness of Surgical Approaches for Lung Cancer.

J Surg Res 2021 07 9;263:274-284. Epub 2020 Dec 9.

Division of Thoracic Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Electronic address:

Background: The magnitude of association and quality of evidence comparing surgical approaches for lung cancer resection has not been analyzed. This has resulted in conflicting information regarding the relative superiority of the different approaches and disparate opinions on the optimal surgical treatment. We reviewed and systematically analyzed all published data comparing near- (30-d) and long-term mortality for minimally invasive to open surgical approaches for lung cancer.

Methods: Comprehensive search of EMBASE, MEDLINE, and the Cochrane Library, from January 2009 to August 2019, was performed to identify the studies and those that passed bias assessment were included in the analysis utilizing propensity score matching techniques. Meta-analysis was performed using random-effects and fixed-effects models. Risk of bias was assessed via the Newcastle-Ottawa Scale and the ROBINS-I tool. The study was registered in PROSPERO (CRD42020150923) prior to analysis.

Results: Overall, 1382 publications were identified but 19 studies were included encompassing 47,054 patients after matching. Minimally invasive techniques were found to be superior with respect to near-term mortality in early and advanced-stage lung cancer (risk ratio 0.45, 95% confidence interval [CI] 0.21-0.95, I = 0%) as well as for elderly patients (odds ratio 0.45, 95% CI 0.31-0.65, I = 30%), but did not demonstrate benefit for high-risk patients (odds ratio 0.74, 95% CI 0.06-8.73, I = 78%). However, no difference was found in long-term survival.

Conclusions: We performed the first systematic review and meta-analysis to compare surgical approaches for lung cancer which indicated that minimally invasive techniques may be superior to thoracotomy in near-term mortality, but there is no difference in long-term outcomes.
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http://dx.doi.org/10.1016/j.jss.2020.10.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169528PMC
July 2021

Improving the informativeness of Mendelian disease-derived pathogenicity scores for common disease.

Nat Commun 2020 12 7;11(1):6258. Epub 2020 Dec 7.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.

Despite considerable progress on pathogenicity scores prioritizing variants for Mendelian disease, little is known about the utility of these scores for common disease. Here, we assess the informativeness of Mendelian disease-derived pathogenicity scores for common disease and improve upon existing scores. We first apply stratified linkage disequilibrium (LD) score regression to evaluate published pathogenicity scores across 41 common diseases and complex traits (average N = 320K). Several of the resulting annotations are informative for common disease, even after conditioning on a broad set of functional annotations. We then improve upon published pathogenicity scores by developing AnnotBoost, a machine learning framework to impute and denoise pathogenicity scores using a broad set of functional annotations. AnnotBoost substantially increases the informativeness for common disease of both previously uninformative and previously informative pathogenicity scores, implying that Mendelian and common disease variants share similar properties. The boosted scores also produce improvements in heritability model fit and in classifying disease-associated, fine-mapped SNPs. Our boosted scores may improve fine-mapping and candidate gene discovery for common disease.
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http://dx.doi.org/10.1038/s41467-020-20087-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721881PMC
December 2020

Management of Total Transection of Nasoendotracheal Tube during LeFort I Osteotomy.

Case Rep Anesthesiol 2020 17;2020:2097240. Epub 2020 Nov 17.

Department of Oral and Maxillofacial Surgery, Prince of Wales Hospital, Randwick, NSW, Australia.

Transection of the nasoendotracheal tube during orthognathic surgery is a rare, but life-threatening complication. We present a case of complete nasoendotracheal tube transection during a LeFort 1 osteotomy and discuss appropriate preventative and management techniques.
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http://dx.doi.org/10.1155/2020/2097240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685862PMC
November 2020

Lung transplantation for patients with severe COVID-19.

Sci Transl Med 2020 12 30;12(574). Epub 2020 Nov 30.

Division of Pulmonary and Critical Care Medicine, Northwestern Memorial Hospital, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

Lung transplantation can potentially be a life-saving treatment for patients with nonresolving COVID-19-associated respiratory failure. Concerns limiting lung transplantation include recurrence of SARS-CoV-2 infection in the allograft, technical challenges imposed by viral-mediated injury to the native lung, and the potential risk for allograft infection by pathogens causing ventilator-associated pneumonia in the native lung. Additionally, the native lung might recover, resulting in long-term outcomes preferable to those of transplant. Here, we report the results of lung transplantation in three patients with nonresolving COVID-19-associated respiratory failure. We performed single-molecule fluorescence in situ hybridization (smFISH) to detect both positive and negative strands of SARS-CoV-2 RNA in explanted lung tissue from the three patients and in additional control lung tissue samples. We conducted extracellular matrix imaging and single-cell RNA sequencing on explanted lung tissue from the three patients who underwent transplantation and on warm postmortem lung biopsies from two patients who had died from COVID-19-associated pneumonia. Lungs from these five patients with prolonged COVID-19 disease were free of SARS-CoV-2 as detected by smFISH, but pathology showed extensive evidence of injury and fibrosis that resembled end-stage pulmonary fibrosis. Using machine learning, we compared single-cell RNA sequencing data from the lungs of patients with late-stage COVID-19 to that from the lungs of patients with pulmonary fibrosis and identified similarities in gene expression across cell lineages. Our findings suggest that some patients with severe COVID-19 develop fibrotic lung disease for which lung transplantation is their only option for survival.
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http://dx.doi.org/10.1126/scitranslmed.abe4282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050952PMC
December 2020

Lung transplantation for pulmonary fibrosis secondary to severe COVID-19.

medRxiv 2020 Oct 27. Epub 2020 Oct 27.

Lung transplantation can potentially be a life-saving treatment for patients with non-resolving COVID-19 acute respiratory distress syndrome. Concerns limiting transplant include recurrence of SARS-CoV-2 infection in the allograft, technical challenges imposed by viral-mediated injury to the native lung, and potential risk for allograft infection by pathogens associated with ventilator-induced pneumonia in the native lung. Additionally, the native lung might recover, resulting in long-term outcomes preferable to transplant. Here, we report the results of the first two successful lung transplantation procedures in patients with non-resolving COVID-19 associated acute respiratory distress syndrome in the United States. We performed smFISH to detect both positive and negative strands of SARS-CoV-2 RNA in the explanted lung tissue, extracellular matrix imaging using SHIELD tissue clearance, and single cell RNA-Seq on explant and warm post-mortem lung biopsies from patients who died from severe COVID-19 pneumonia. Lungs from patients with prolonged COVID-19 were free of virus but pathology showed extensive evidence of injury and fibrosis which resembled end-stage pulmonary fibrosis. Single cell RNA-Seq of the explanted native lungs from transplant and paired warm post-mortem autopsies showed similarities between late SARS-CoV-2 acute respiratory distress syndrome and irreversible end-stage pulmonary fibrosis requiring lung transplantation. There was no recurrence of SARS-CoV-2 or pathogens associated with pre-transplant ventilator associated pneumonias following transplantation in either patient. Our findings suggest that some patients with severe COVID-19 develop fibrotic lung disease for which lung transplantation is the only option for survival.

Single Sentence Summary: Some patients with severe COVID-19 develop end-stage pulmonary fibrosis for which lung transplantation may be the only treatment.
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http://dx.doi.org/10.1101/2020.10.26.20218636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605582PMC
October 2020
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