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We present a patient with a history of lung transplantation who subsequently underwent dual heart-kidney transplantation for nonischemic cardiomyopathy and chronic kidney disease, becoming one of the rare cases of triple-organ transplantation. This case underscores the evolving challenges and successes in managing complex transplant recipients.

BACKGROUND: Lung transplant surgery creates surgical pulmonary vein isolation (PVI) as a routine part of the procedure. However, many patients with pretransplant atrial fibrillation continue to have atrial fibrillation at 1 y. We hypothesized that the addition of electrical PVI and left atrial appendage isolation/ligation (LAL) to the lung transplant procedure restores sinus rhythm at 1 y in patients with pretransplant atrial fibrillation. METHODS: We retrospectively reviewed all adult lung transplant recipients at the University of California Los Angeles from April 2006 to August 2021. All patients with pretransplant atrial fibrillation underwent concomitant PVI/LAL and were compared with lung transplant recipients without preoperative atrial fibrillation. In-hospital outcomes; 1-y survival; and the incidence of stroke, cardiac readmissions, repeat ablations, and sinus rhythm (composite endpoint) were examined at 1 y for the PVI/LAL cohort. RESULTS: Sixty-one lung transplant recipients with pretransplant atrial fibrillation underwent concomitant PVI/LAL. No patient in the PVI/LAL cohort required cardiac-related readmission or catheter ablation for atrial fibrillation within 1 y of transplantation. Freedom from the composite endpoint of death, stroke, cardiac readmission, and repeat ablation for atrial fibrillation at 1 y was 85% (95% confidence interval, 73%-92%) for lung transplant recipients treated with PVI/LAL. CONCLUSIONS: The addition of PVI/LAI to the lung transplant operation in patients with pretransplant atrial fibrillation was safe and effective in maintaining sinus rhythm and baseline risk of stroke at 1 y.

OBJECTIVE: We aimed to evaluate the safety and efficacy of delaying lung transplantation until morning for donors with cross-clamp times occurring after 1:30 am. METHODS: All consented adult lung transplant recipients between March 2018 and May 2022 with donor cross-clamp times between 1:30 am and 5 am were enrolled prospectively in this study. Skin incision for enrolled recipients was delayed until 6:30 am (Night group). The control group was identified using a 1:2 logistic propensity score method and included recipients of donors with cross-clamp times occurring at any other time of day (Day group). Short- and medium-term outcomes were examined between groups. The primary endpoint was early mortality (30-day and in-hospital). RESULTS: Thirty-four patients were enrolled in the Night group, along with 68 well-matched patients in the Day group. As expected, donors in the Night group had longer cold ischemia times compared to the Day group (344 minutes vs 285 minutes; P

Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.

Backgound: Older lung transplant recipients experience increased rates of adverse clinical outcomes, including infection compared with younger patients, potentially related to impaired cell-mediated immunity, frailty, and sarcopenia. Methods: Patients over age 55 years undergoing evaluation for lung transplantation were evaluated for sarcopenia by cross-sectional area and average attenuation of the pectoralis major muscle on chest computed tomography. Frailty was measured using the Fried Frailty Phenotype. Immune phenotyping was performed using multichannel flow cytometry of peripheral blood mononuclear cells (PBMC) in a total of 26 lung transplant candidates. Results: The median patient age was 65, primarily with restrictive lung disease (76.9%). Hospital readmission was associated with lower frequency of naïve CD4 (p = 0.004) and CD8 T cells (p = 0.026). Senescent CD4 (KLRG1+/CD28−) and CD8 T cells were also associated with readmission (p = 0.014 and p = 0.013, respectively), and senescent CD4 T cells were predictive of total hospital time (p = 0.003). TEMRA CD4 T cells were significantly associated with frailty (p = 0.015) and sarcopenia (p = 0.011). Senescent CD4 and CD8 T cells were significantly associated with sarcopenia (p = 0.009 and p = 0.006, respectively). Conclusions: These findings suggest that impaired cell-mediated immunity may underlie the associations between frailty and sarcopenia and poor clinical outcomes. A multifaceted approach to evaluation of older patients has the potential to improve risk stratification and inform management of immunosuppression.

Introduction The relationship between food insecurity and access to healthcare in low-resource settings remains unclear. Some studies find that food insecurity is a barrier to accessing care, while others report that food insecurity is associated with a greater need for care, leading to more care utilisation. We use data from the Harambee study in western Kenya to assess the association between food insecurity and difficulty accessing care among people living with HIV (PLWH) with or without comorbid non-communicable diseases (NCDs).Methods The Harambee study is a cluster randomised trial that tested the effectiveness of delivering integrated HIV and NCD care for PLWH. In this cross-sectional analysis, we examined baseline data from Harambee participants to investigate the relationship between household food insecurity and difficulty accessing care, using multivariable logistic regression models, controlling for sociodemographic factors and care satisfaction. We tested for effect measure modification by gender and household wealth and stratified analyses by NCD status.Results Among 1039 participants, 11.1% reported difficulty accessing care, and 18.9% and 51.9% of participants had moderate and severe food insecurity, respectively. Among those with difficulty accessing care, 73.9% cited transportation issues as the major barrier. Difficulty accessing care was greater with higher levels of food insecurity: among participants with low, moderate and severe food insecurity, 5.9%, 9.7% and 14.4% reported difficulty accessing care, respectively. After adjusting for confounders, severe food insecurity was independently associated with difficulty accessing care (adjusted OR=2.5, 95% CI 1.4 to 4.4). There was no statistical evidence for effect measure modification by gender or wealth.Conclusions We found that greater food insecurity was associated with greater difficulty accessing care among PLWH with or without NCDs in rural western Kenya. These findings suggest that addressing social determinants of health may be necessary when implementing integrated HIV and NCD care programmes.

Using DNA methylation profiles (n = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels in HOXL subclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors. The methylation state of some modules responds to perturbations such as caloric restriction, ablation of growth hormone receptors, consumption of high-fat diets, and expression of Yamanaka factors. This study reveals an intertwined evolution of the genome and epigenome that mediates the biological characteristics and traits of different mammalian species.

Despite the prevalence of pericytes in the microvasculature of the heart, their role during ischemia-induced remodeling remains unclear. We used multiple lineage-tracing mouse models and found that pericytes migrated to the injury site and expressed profibrotic genes, coinciding with increased vessel leakage after myocardial infarction (MI). Single-cell RNA-Seq of cardiac pericytes at various time points after MI revealed the temporally regulated induction of genes related to vascular permeability, extracellular matrix production, basement membrane degradation, and TGF-β signaling. Deleting TGF-β receptor 1 in chondroitin sulfate proteoglycan 4-expressing (Cspg4-expressing) cells reduced fibrosis following MI, leading to a transient improvement in the cardiac ejection fraction. Furthermore, genetic ablation of Cspg4-expressing cells resulted in excessive vascular permeability, a decline in cardiac function, and increased mortality in the second week after MI. These data reveal an essential role for cardiac pericytes in the control of vascular homeostasis and the fibrotic response after acute ischemic injury, information that will help guide the development of novel strategies to preserve vascular integrity and attenuate pathological cardiac remodeling.

BACKGROUND: As lung transplantation (LT) expands to older recipients, objective approaches to evaluate the aging are needed to optimize posttransplantation outcomes. Frailty assessment and sarcopenia have shown promise as tools for predicting clinical outcomes. METHODS: Patients older than 55 years undergoing evaluation for LT were enrolled in an institutional review board-approved study. Sarcopenia was measured on pretransplantation chest computed tomography images, measuring cross-sectional area and average attenuation of the pectoralis major muscle at 1 slice above the aortic arch. Frailty was measured using the Fried frailty phenotype (FFP) and Short Performance Physical Battery (SPPB). RESULTS: The study evaluated 84 patients with results of computed tomography of the chest available for review; 63% were classified as frail or prefrail by SPPB and 53% were frail by FFP. Sex-corrected sarcopenia was associated with frailty by FFP (P = .004) or SPPB (P = .044). Sarcopenia, measured by area or average attenuation, was significantly associated with length of stay after transplantation (P = .017 and P = .022, respectively), with a median 12 days for those with higher muscle mass compared with 21 days for those with lower muscle mass. Total time in the hospital in the first year after transplantation was also associated with sarcopenia by area (P = .090) or average attenuation (P = .046). CONCLUSIONS: A multifaceted approach to the evaluation of older patients can improve risk stratification, optimizing organ allocation to improve LT outcomes.

The Lasker Foundation has awarded the 2024 Lasker~DeBakey Clinical Medical Research Award to Joel Habener (Massachusetts General Hospital), Svetlana Mojsov (Rockefeller University), and Lotte Bjerre Knudsen (Novo Nordisk) for their [...]

Type 2 diabetes (T2D) affects millions of individuals worldwide and is a well-documented risk factor for cardiovascular (CV) disease and chronic kidney disease, both of which are leading causes of mortality. Racial and ethnic minority groups in the US, including but not limited to Hispanic/Latino, non-Hispanic Black, and Southeast Asian individuals, are disproportionately burdened by both T2D and its adverse outcomes. In recent years, there have been numerous cardiovascular outcomes trials (CVOTs) on novel antidiabetic therapies, including the dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), and sodium-glucose cotransporter-2 (SGLT2) inhibitors. CVOTs’s initial aim was to demonstrate the cardiovascular safety of these drugs. Unexpected CV and kidney protective effects were found, specifically among the GLP-1 RAs and the SGLT2 inhibitors. These benefits informed the new paradigm of the management of patients with T2D. However, some experts argued that the lack of racial and ethnic minority group representation in these trials represented a challenge. While the downstream effects of this lack of representation must be further elucidated, it is clear and recognized that efforts need to be made to include a more representative sample in future CVOTs, specifically including individuals from those groups most burdened by T2D and its complications, if clinicians are to have an accurate picture of the benefits and potential pitfalls of utilizing these drugs in a real-world setting. In this comprehensive review, we briefly summarize the significant findings from the CVOTs, report the lack of representation of Hispanic/Latino, non-Hispanic Black, and Southeast Asian individuals in the CVOTs, investigate the barriers to recruiting racial and ethnic minority groups into clinical trials, and suggest potential solutions to overcome these obstacles at the patient-, provider-, and sponsor/system-level in future trials.

Heart failure with preserved ejection fraction (HFpEF) is commonly found in persons living with HIV (PLWH) even when antiretroviral therapy suppresses HIV viremia. However, studying this condition has been challenging because an appropriate animal model is not available. In this article, we studied calcium transient in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in culture to simulate the cardiomyocyte relaxation defect noted in PLWH and HFpEF and assess whether various drugs have an effect. We show that treatment of hiPSC-CMs with inflammatory cytokines (such as interferon-γ or TNF-α) impairs their Ca2+ uptake into sarcoplasmic reticulum and that SGLT2 inhibitors, clinically proven as effective for HFpEF, reverse this effect. Additionally, treatment with mitochondrial antioxidants (like mito-Tempo) and certain antiretrovirals resulted in the reversal of the effects of these cytokines on calcium transient. Finally, incubation of hiPSC-CMs with serum from HIV patients with and without diastolic dysfunction did not alter their Ca2+-decay time, indicating that the exposure to the serum of these patients is not sufficient to induce the decrease in Ca2+ uptake in vitro. Together, our results indicate that hiPSC-CMs can be used as a model to study molecular mechanisms of inflammation-mediated abnormal cardiomyocyte relaxation and screen for potential new interventions.

Clinical outcomes after lung transplantation, a life-saving therapy for patients with end-stage lung diseases, are limited by primary graft dysfunction (PGD). PGD is an early form of acute lung injury with no specific pharmacologic therapies. Here, we present a large multicenter study of plasma and bronchoalveolar lavage (BAL) samples collected on the first posttransplant day, a critical time for investigations of immune pathways related to PGD. We demonstrated that ligands for NKG2D receptors were increased in the BAL from participants who developed severe PGD and were associated with increased time to extubation, prolonged intensive care unit length of stay, and poor peak lung function. Neutrophil extracellular traps (NETs) were increased in PGD and correlated with BAL TNF-α and IFN-γ cytokines. Mechanistically, we found that airway epithelial cell NKG2D ligands were increased following hypoxic challenge. NK cell killing of hypoxic airway epithelial cells was abrogated with NKG2D receptor blockade, and TNF-α and IFN-γ provoked neutrophils to release NETs in culture. These data support an aberrant NK cell/neutrophil axis in human PGD pathogenesis. Early measurement of stress ligands and blockade of the NKG2D receptor hold promise for risk stratification and management of PGD.

The COVID-19 pandemic led to changes in heart transplantation, including transitioning from in-person to virtual selection committee meetings. The longer-term impact of this transition on committee perceptions and patient selection outcomes has not been described. An anonymous survey was administered to our institution’s selection committee. Among 58 regular attendees, there were 21 physician and 21 nonphysician respondents. Selection outcomes were compared for patients discussed during in-person meetings (March 1, 2017-March 14, 2020) with those of virtual meetings (March 15, 2020-March 31, 2023). Though a virtual format was generally preferred, respondents highlighted a lack of accountability and spontaneous discussion. Among the 529 patients evaluated during the study period, there was a significant difference in selection outcomes between the virtual and in-person cohorts owing to lower rates of deferral and higher rates of approval in the virtual era overall (p = 0.009) and notably among men, but not women (p = 0.022).

Implantable cardiac patches and injectable hydrogels are among the most promising therapies for cardiac tissue regeneration following myocardial infarction. Incorporating electrical conductivity into these patches and hydrogels is found to be an efficient method to improve cardiac tissue function. Conductive nanomaterials such as carbon nanotube, graphene oxide, gold nanorod, as well as conductive polymers such as polyaniline, polypyrrole, and poly(3,4-ethylenedioxythiophene):polystyrene sulfonate are appealing because they possess the electroconductive properties of semiconductors with ease of processing and have potential to restore electrical signaling propagation through the infarct area. Numerous studies have utilized these materials for regeneration of biological tissues that possess electrical activities, such as cardiac tissue. In this review, recent studies on the use of electroconductive materials for cardiac tissue engineering and their fabrication methods are summarized. Moreover, recent advances in developing electroconductive materials for delivering therapeutic agents as one of emerging approaches for treating heart diseases and regenerating damaged cardiac tissues are highlighted.

Abstract We consider the 𝒩 = (2, 2) AdS3/CFT2 dualities proposed by Eberhardt, where the bulk geometry is AdS3 × (S 3 × T 4)/ℤ k , and the CFT is a deformation of the symmetric orbifold of the supersymmetric sigma model T 4/ℤ k (with k = 2, 3, 4, 6). The elliptic genera of the two sides vanish due to fermionic zero modes, so for microstate counting applications one must consider modified supersymmetric indices. In an analysis similar to that of Maldacena, Moore, and Strominger for the standard 𝒩 = (4, 4) case of T 4, we study the appropriate helicity-trace index of the boundary CFTs. We encounter a strange phenomenon where a saddle-point analysis of our indices reproduces only a fraction (respectively 1 2 $$ \frac{1}{2} $$ , 2 3 $$ \frac{2}{3} $$ , 3 4 $$ \frac{3}{4} $$ , 5 6 $$ \frac{5}{6} $$ ) of the Bekenstein-Hawking entropy of the associated macroscopic black branes.

Objective: We aimed to evaluate the safety and efficacy of delaying lung transplantation until morning for donors with cross-clamp times occurring after 1:30 am. Methods: All consented adult lung transplant recipients between March 2018 and May 2022 with donor cross-clamp times between 1:30 am and 5 am were enrolled prospectively in this study. Skin incision for enrolled recipients was delayed until 6:30 am (Night group). The control group was identified using a 1:2 logistic propensity score method and included recipients of donors with cross-clamp times occurring at any other time of day (Day group). Short- and medium-term outcomes were examined between groups. The primary endpoint was early mortality (30-day and in-hospital). Results: Thirty-four patients were enrolled in the Night group, along with 68 well-matched patients in the Day group. As expected, donors in the Night group had longer cold ischemia times compared to the Day group (344 minutes vs 285 minutes; P

Newborn mammalian cardiomyocytes quickly transition from a fetal to an adult phenotype that utilizes mitochondrial oxidative phosphorylation but loses mitotic capacity. We tested whether forced reversal of adult cardiomyocytes back to a fetal glycolytic phenotype would restore proliferative capacity. We deleted Uqcrfsl (mitochondrial Rieske iron- sulfur protein, RISP) in hearts of adult mice. As RISP protein decreased, heart mitochondrial function declined, and glucose utilization increased. Simultaneously, the hearts underwent hyperplastic remodeling during which cardiomyocyte number doubled without cellular hypertrophy. Cellular energy supply was preserved, AMPK activation was absent, and mTOR activation was evident. In ischemic hearts with RISP deletion, new cardiomyocytes migrated into the infarcted region, suggesting the potential for therapeutic cardiac regeneration. RNA sequencing revealed upregulation of genes associated with cardiac development and proliferation. Metabolomic analysis revealed a decrease in a-ketoglutarate (required for TET-mediated demethylation) and an increase in 5-adenosylmethionine (required for methyltransferase activity). Analysis revealed an increase in methylated CpGs near gene transcriptional start sites. Genes that were both differentially expressed and differentially methylated were linked to upregulated cardiac developmental pathways. We conclude that decreased mitochondrial function and increased glucose utilization can restore mitotic capacity in adult cardiomyocytes, resulting in the generation of new heart cells, potentially through the modification of substrates that regulate epigenetic modification of genes required for proliferation., Introduction Mitochondria generate ATP through oxidative phosphorylation (OXPHOS), but they also participate in diverse biological functions that include redox signaling (1), metabolite signaling (2), calcium signaling (3), and the generation [...]

Immune cells have emerged as powerful regulators of regenerative as well as pathological processes. The vast majority of regenerative immunoengineering efforts have focused on macrophages; however, growing evidence suggests that other cells of both the innate and adaptive immune system are as important for successful revascularization and tissue repair. Moreover, spatiotemporal regulation of immune cells and their signaling have a significant impact on the regeneration speed and the extent of functional recovery. In this review, we summarize the contribution of different types of immune cells to the healing process and discuss ways to manipulate and control immune cells in favor of vascularization and tissue regeneration. In addition to cell delivery and cell-free therapies using extracellular vesicles, we discuss in situ strategies and engineering approaches to attract specific types of immune cells and modulate their phenotypes. This field is making advances to uncover the extraordinary potential of immune cells and their secretome in the regulation of vascularization and tissue remodeling. Understanding the principles of immunoregulation will help us design advanced immunoengineering platforms to harness their power for tissue regeneration.

The ontogeny of human haematopoietic stem cells (HSCs) is poorly defined owing to the inability to identify HSCs as they emerge and mature at different haematopoietic sites1. Here we created a single-cell transcriptome map of human haematopoietic tissues from the first trimester to birth and found that the HSC signature RUNX1+HOXA9+MLLT3+MECOM+HLF+SPINK2+ distinguishes HSCs from progenitors throughout gestation. In addition to the aorta-gonad-mesonephros region, nascent HSCs populated the placenta and yolk sac before colonizing the liver at 6 weeks. A comparison of HSCs at different maturation stages revealed the establishment of HSC transcription factor machinery after the emergence of HSCs, whereas their surface phenotype evolved throughout development. The HSC transition to the liver marked a molecular shift evidenced by suppression of surface antigens reflecting nascent HSC identity, and acquisition of the HSC maturity markers CD133 (encoded by PROM1) and HLA-DR. HSC origin was tracked to ALDH1A1+KCNK17+ haemogenic endothelial cells, which arose from an IL33+ALDH1A1+ arterial endothelial subset termed pre-haemogenic endothelial cells. Using spatial transcriptomics and immunofluorescence, we visualized this process in ventrally located intra-aortic haematopoietic clusters. The in vivo map of human HSC ontogeny validated the generation of aorta-gonad-mesonephros-like definitive haematopoietic stem and progenitor cells from human pluripotent stem cells, and serves as a guide to improve their maturation to functional HSCs.

IntroductionFrailty status affects outcomes after heart transplantation, but the optimal way to assess frailty prior to transplant remains unknown.MethodsThis single-center, observational study assessed 44 heart transplant candidates for frailty using three methods. The Short Physical Performance Battery (SPPB) and Fried Frailty Phenotype (FFP) were used as two physical assessments of frailty. The Frailty Risk Score (FRS) was used as a chart-review based assessment measuring 20 different biopsychosocial and functional components, including biomarkers, depression, cognitive impairment, and sleep.ResultsWe determined the correlation between FRS, SPPB, and FFP and how each correlated with clinical outcomes. Of 44 participants, mean age was 60 years. FRS correlated with SPPB and FFP (P = .043, P

BackgroundHeart transplant selection committee meetings have transitioned from in-person to remote video meetings during the COVID-19 pandemic, but how this impacts committee members and patient outcomes is unknown.ObjectiveThe aim of this study is to determine the perceived impact of remote video transplant selection meetings on usability and patient care and to measure patient selection outcomes during the transition period from in-person to virtual meetings.MethodsA 35-item anonymous survey was developed and distributed electronically to the heart transplant selection committee. We reviewed medical records to compare the outcomes of patients presented at in-person meetings (January-March 2020) to those presented during video meetings (March-June 2020).ResultsAmong 83 committee members queried, 50 were regular attendees. Of the 50 regular attendees, 24 (48%) were physicians and 26 (52%) were nonphysicians, including nurses, social workers, and coordinators; 46 responses were received, 23 (50%) from physicians and 23 (50%) from nonphysicians, with 41 responses fully completed. Overall, respondents were satisfied with the videoconference format and felt that video meetings did not impact patient care and were an acceptable alternative to in-person meetings. However, 54% (22/41) preferred in-person meetings, with 71% (15/21) of nonphysicians preferring in-person meetings compared to only 35% (7/20) of physicians (P=.02). Of the 46 new patient evaluations presented, there was a statistically nonsignificant trend toward fewer patients initially declined at video meetings compared with in-person meetings (6/24, 25% compared to 10/22, 45%; P=.32).ConclusionsThe transition from in-person to video heart transplant selection committee meetings was well-received and did not appear to affect committee members' perceived ability to deliver patient care. Patient selection outcomes were similar between meeting modalities.

AimsWe prospectively isolate and characterize first and second heart field- and nodal-like cardiomyocytes using a double reporter line from human embryonic stem cells. Our double reporter line utilizes two important transcription factors in cardiac development, TBX5 and NKX2-5. TBX5 expression marks first heart field progenitors and cardiomyocytes while NKX2-5 is expressed in nearly all myocytes of the developing heart (excluding nodal cells). We address the shortcomings of prior work in the generation of heart field-specific cardiomyocytes from induced pluripotent stem cells and provide a comprehensive early developmental transcriptomic as well as electrophysiological analyses of these three populations.Methods and resultsTranscriptional, immunocytochemical, and functional studies support the cellular identities of isolated populations based on the expression pattern of NKX2-5 and TBX5. Importantly, bulk and single-cell RNA sequencing analyses provide evidence of unique molecular signatures of isolated first and second heart field cardiomyocytes, as well as nodal-like cells. Extensive electrophysiological analyses reveal dominant atrial action potential phenotypes in first and second heart fields in alignment with our findings in single-cell RNA sequencing. Lastly, we identify two novel surface markers, POPDC2 and CORIN, that enable purification of cardiomyocytes and first heart field cardiomyocytes, respectively.ConclusionsWe describe a high-yield approach for isolation and characterization of human embryonic stem cell-derived heart field-specific and nodal-like cardiomyocytes. Obtaining enriched populations of these different cardiomyocyte subtypes increases the resolution of gene expression profiling during early cardiogenesis, arrhythmia modelling, and drug screening. This paves the way for the development of effective stem cell therapy to treat diseases that affect specific regions of the heart- or chamber-specific congenital heart defects.

Despite the common detection of non-donor specific anti-HLA antibodies (non-DSAs) after lung transplantation, their clinical significance remains unclear. In this retrospective single-center cohort study of 325 lung transplant recipients, we evaluated the association between donor-specific HLA antibodies (DSAs) and non-DSAs with subsequent CLAD development. DSAs were detected in 30% of recipients and were associated with increased CLAD risk, with higher HRs for both de novo and high MFI (>5000) DSAs. Non-DSAs were detected in 56% of recipients, and 85% of DSA positive tests had concurrent non-DSAs. In general, non-DSAs did not increase CLAD risk in multivariable models accounting for DSAs. However, non-DSAs in conjunction with high BAL CXCL9 levels were associated with increased CLAD risk. Multivariable proportional hazards models demonstrate the importance of the HLA antibody-CXCL9 interaction: CLAD risk increases when HLA antibodies (both DSAs and non-DSAs) are detected in conjunction with high CXCL9. Conversely, CLAD risk is not increased when HLA antibodies are detected with low CXCL9. This study supports the potential utility of BAL CXCL9 measurement as a biomarker to risk stratify HLA antibodies for future CLAD. The ability to discriminate between high versus low-risk HLA antibodies may improve management by allowing for guided treatment decisions.

IntroductionThe impact of colchicine on hospitalized patients with Coronavirus disease-19 (COVID-19) related cardiac injury is unknown.Materials and methodsIn this multicenter randomized controlled open-label clinical trial, we randomized hospitalized adult patients with documented COVID-19 and evidence of cardiac injury in a 1:1 ratio to either colchicine 0.6 mg po twice daily for 30 days plus standard of care or standard of care alone. Cardiac injury was defined as elevated cardiac biomarkers, new arrhythmia, new/worsened left ventricular dysfunction, or new pericardial effusion. The primary endpoint was the composite of all-cause mortality, need for mechanical ventilation, or need for mechanical circulatory support (MCS) at 90 days. Key secondary endpoints included the individual components of the primary endpoint and change in and at least 2-grade reduction in the World Health Organization (WHO) Ordinal Scale at 30 days. The trial is registered with clinicaltrials.gov (NCT04355143).ResultsWe enrolled 93 patients, 48 patients in the colchicine arm and 45 in the control arm. There was no significant difference in the primary outcome between the colchicine and control arms (19 vs. 15%, p = 0.78), nor in the individual components of all-cause mortality (17 vs. 15%, p = 1.0) and need for mechanical ventilation (8 vs. 5%, p = 0.68); no patients in either group required MCS. The change in (-1.8 ± 2.4 vs. -1.2 ± 2.0, p = 0.12) and at least 2-grade reduction (75 vs. 75%, p = 1.0) in the WHO ordinal scale was also similar between groups.ConclusionPatients hospitalized with COVID-19 and evidence of cardiac injury did not benefit from colchicine therapy.

Venovenous (VV) extracorporeal membrane oxygenation (ECMO) has been used as a bridge to lung transplantation with acceptable outcomes. We hypothesized that venoarterial (VA) ECMO, as part of a multidisciplinary ECMO program, yields similar outcomes as VV ECMO as a bridge in lung transplantation.Records of all patients who had undergone ECMO with the intention to bridge to lung transplantation at University of California, Los Angeles, from January 1, 2012, to March 31, 2020, were reviewed. Baseline characteristics, in-hospital outcomes, long-term survival, and freedom from bronchiolitis obliterans syndrome were assessed.During this interval, 58 patients were placed on ECMO with the intention to bridge to lung transplantation: 27 on VV ECMO, and 31 on VA ECMO, with a median duration of 7 and 17 days of support, respectively (P = .01). Successful bridge to lung transplantation occurred in 21 VV patients (78%) and in 26 VA patients (84%). Incidence of primary graft dysfunction III at 72 hours in the VV and the VA cohorts was 0% and 4%, respectively (P = .99). In-hospital and 90-day survival of the VV and VA groups was 100% and 96%, respectively (P = .99). Survival of the 2 groups at 3 years was not significantly different from a contemporary cohort of lung transplant recipients not bridged with ECMO.VA and VV ECMO can both be used as a bridge to lung transplantation with high success, with short and medium-term survival similar to non-bridged lung transplant recipients. Both modes should be considered effective at bridging select candidates to lung transplantation.