Single nucleus transcriptomics supports a role for CCNA2-induced human adult cardiomyocyte cytokinesis.

Cyclin A2 (CCNA2) is a master regulatory gene of the cell cycle that is normally silenced in postnatal mammalian cardiomyocytes. We have previously demonstrated that it can induce significant cardiac repair in both small and large animals when delivered to the heart via a viral vector. To date, whether CCNA2 gene delivery can induce cytokinesis in isolated cardiomyocytes from adult human hearts has not been investigated. Therefore, we designed a human gene therapy vector featuring a replication-deficient, E1/E3-deleted human adenovirus five encoding human CCNA2 driven by the cardiac Troponin T promoter to enable the expression of CCNA2 in freshly isolated human cardiomyocytes. Utilizing time-lapse microscopy live imaging of cultured adult human cardiomyocytes isolated from a 21-year-old male, 41-year-old female, and 55-year-old male, we now report that human adult cardiomyocytes can be induced to undergo complete cytokinesis in response to CCNA2 gene delivery with preservation of sarcomere integrity in the resulting daughter cells. To elucidate the mechanistic underpinnings of CCNA2-dependent gene regulation in governing cardiomyocyte cytokinesis, we conducted single nucleus transcriptomics (snRNA-seq, 10X Genomics) analysis in hearts isolated from adult transgenic mice that constitutively express CCNA2 in cardiomyocytes (CCNA2-Tg) and non-transgenic mice (nTg). Remarkably, we identified a subpopulation of cardiomyocytes enriched with cytokinesis, proliferative, and reprogramming genes in hearts obtained from CCNA2-Tg mice as compared to hearts obtained from nTg mice. We also performed bulk RNA sequencing of human adult and fetal hearts, and we identified key reprogramming genes that are involved in CCNA2-induced cytokinesis. These results provide a compelling path forward for the clinical development of cardiac regenerative therapy based on strategic manipulation of the cardiomyocyte cell cycle.

Pop-Out Myocardial Infarction Induction in Mice.

Myocardial infarction (MI) in mice is a widely used surgical model in preclinical cardiac repair studies to recapitulate human cardiovascular ischemic disease. Induction of reproducible infarct size is crucial for quantitative and analytical purpose. Here we describe a quick and reliable method to induce consistent infarct size in mice in less than a minute.

Discovery of a multipotent cell type from the term human placenta.

We report a unique population of multipotent cells isolated from the term human placenta, for the first time, that can differentiate into cardiomyocytes and vascular cells with clonal proliferative ability, migratory ability, and trancriptomic evidence of immune privilege. Caudal-type homeobox-2 (CDX2) is a conserved factor that regulates trophectoderm formation and placentation during early embryonic development but has not previously been implicated in developmentally conserved regenerative mechanisms. We had earlier reported that Cdx2 lineage cells in the mouse placenta are capable of restoring cardiac function after intravenous delivery in male mice with experimental cardiac injury (myocardial infarction). Here we demonstrate that CDX2-expressing cells are prevalent in the human chorion and are poised for cardiovascular differentiation. We examined the term placentas from 106 healthy patients and showed that isolated CDX2 cells can spontaneously differentiate into cardiomyocytes, functional vascular cells, and retain homing ability in vitro. Functional annotation from transcriptomics analysis supports enhanced cardiogenesis, vasculogenesis, immune modulation, and chemotaxis gene signatures in CDX2 cells. CDX2 cells can be clonally propagated in culture with retention of cardiovascular differentiation. Our data supports further use of this accessible and ethically feasible cell source in the design of therapeutic strategies for cardiovascular disease.

Ultrastructural insights from myocardial ablation lesions from microsecond pulsed field vs radiofrequency energy.

BACKGROUND: Ultrastructural findings immediately after pulsed field ablation (PFA) of the myocardium have not been described. OBJECTIVES: The purpose of this study was to elucidate ultrastructural characteristics and differences between microsecond PFA at the 1- and 4-hour timepoints after pulse delivery and to compare them to irrigated radiofrequency ablation (RFA) lesions. METHODS: Healthy swine underwent endocardial PFA or RFA followed by necropsy. Discrete microsecond PFA and irrigated RFA lesions were created in the ventricles with a lattice tip ablation catheter. Lesions were delivered in a manner so as to allow sampling to occur 1 and 4 hours after ablation. All lesions were located at necropsy, and samples were carefully obtained from within the lesion core, lesion periphery, and adjacent healthy myocardium. Transmission electron microscopic assessment was performed after fixation using paraformaldehyde and glutaraldehyde. RESULTS: One hour after microsecond PFA delivery, myocytes were noted to be significantly and uniformly disrupted. Clustered, misaligned, swollen mitochondria coupled with degenerating nuclei and condensed chromatin were visualized. These findings progressed over the subsequent few hours with worsening edema. Similar changes were seen with RFA but reduced in severity. However, there was prominent extravasation of red blood cells with occlusion of capillaries that was not seen in PFA. At the lesion periphery, an abrupt change in the degree of myocyte damage was observed with PFA but not RFA. CONCLUSION: Transmission electron microscopy demonstrates evidence of widespread destruction of myocytes as early as an hour after PFA and corroborates known histologic features such as sparing of vessels and sharp lesion margins.

A new strategy for cardiac protection.

It may be possible to treat cardiac hypertrophy and injury by using drugs that inhibit a protein called SIRT2.

Regulation of Cardiomyocyte Division During Cardiac Regeneration.

PURPOSE OF REVIEW: This review explores efforts made over the previous three decades to determine mechanisms of cardiomyocyte cell division. Many investigators have explored cell therapy strategies in animal models and clinical trials over the past 2 decades with marginal results thus far in clinical testing. Hence, there is a greater focus now on strategies to induce cardiomyocyte proliferation. RECENT FINDINGS: Reports to induce reactivation of the cardiomyocyte cell cycle predated the focus on cell therapy, and we summarize the literature on this topic, which began with the very first transgenic mouse studies in cardiovascular science. These earlier studies form the foundation for the use of cell cycle manipulation in cardiac repair and should inform current and future investigations with respect to rigor of assessment in the degree of cardiomyocyte cell division and gold standard measures of cardiac functional improvement.

Electrophysiology, Pathology, and Imaging of Pulsed Field Ablation of Scarred and Healthy Ventricles in Swine.

BACKGROUND: Pulsed field ablation (PFA) has recently been shown to penetrate ischemic scar, but details on its efficacy, risk of arrhythmias, and imaging insights are lacking. In a porcine model of myocardial scar, we studied the ability of ventricular PFA to penetrate scarred tissue, induce ventricular arrhythmias, and assess the influence of QRS gating during pulse delivery. METHODS: Of a total of 6 swine, 5 underwent coronary occlusion and 1 underwent radiofrequency ablation to create infarct scar and iatrogenic scar models, respectively. Two additional swine served as healthy controls. An 8 Fr focal PFA catheter was used to deliver bipolar, biphasic PFA (2.0 kV) lesions guided by electroanatomical mapping, fluoroscopy, and intracardiac echocardiography over both scarred and healthy myocardium. Swine underwent magnetic resonance imaging 2-7 days post-PFA. RESULTS: PFA successfully penetrated scar without significant difference in lesion depth between lesion at the infarct border (5.9±1.0 mm, n=41) and healthy myocardium (5.7±1.3 mm, n=26; P=0.53). PFA penetration of both infarct and iatrogenic radiofrequency abalation scar was observed in all examined sections. Sustained ventricular arrhythmias requiring defibrillation occurred in 4 of 187 (2.1%) ungated applications, whereas no ventricular arrhythmias occurred during gated PFA applications (0 of 64 [0%]). Dark-blood late-gadolinium-enhanced sequences allowed for improved endocardial border detection as well as lesion boundaries compared with conventional bright-blood late-gadolinium-enhanced sequences. CONCLUSIONS: PFA penetrates infarct and iatrogenic scar successfully to create deep lesions. Gated delivery eliminates the occurrence of ventricular arrhythmias observed with ungated porcine PFA. Optimized magnetic resonance imaging sequences can be helpful in detecting lesion boundaries.

Pulsed Field Ablation of the Porcine Ventricle Using a Focal Lattice-Tip Catheter.

BACKGROUND: Our understanding of catheter-based pulsed field ablation (PFA) of the ventricular myocardium is limited. We conducted a series of exploratory evaluations of ventricular PFA in swine ventricles. METHODS: A focal lattice-tip catheter was used to deliver proprietary biphasic monopolar PFA applications to swine ventricles under general anesthesia, with guidance from electroanatomical mapping, fluoroscopy, and intracardiac echocardiography. We conducted experiments to assess the impact of (1) delivery repetition (2×, 3×, or 4×) at each location, (2) epicardial PFA delivery, and (3) confluent areas of shallow healed endocardial scar created by prior PFA (4 weeks earlier) on subsequent endocardial PFA. Additional assessments included PFA optimized for the ventricle, lesion visualization by intracardiac echocardiography imaging, and immunohistochemical insights. RESULTS: Experiment no. 1: lesions (n=49) were larger with delivery repetition of either 4× or 3× versus 2×: length 17.6±3.9 or 14.2±2.0 versus 12.7±2.0 mm (P<0.01, P=0.22), width 13.4±1.8 or 10.6±1.3 versus 10.5±1.1 mm (P<0.01, P=1.00), and depth 6.1±2.1 or 5.1±1.3 versus 4.2±1.0 mm (P<0.01, P=0.21). Experiment no. 2: epicardial lesions (n=18) were reliably created and comparable to endocardial lesions: length 24.6±9.7 mm (n=5), width 15.6±4.6 mm, and depth 4.5±3.7 mm. Experiment no. 3: PFA (n=16) was able to penetrate to a depth of 4.8 (interquartile range, 4.5-5.4) mm in healthy myocardium versus 5.6 (interquartile range, 3.6-6.6) mm in adjacent healed endocardial scar (P=0.79), suggesting that superficial scar does not significantly impair PFA. Finally, we demonstrate, PFA optimized for the ventricle yielded adequate lesion dimensions, can result in myocardial activation, can be visualized by intracardiac echocardiography, and have unique immunohistochemical characteristics. CONCLUSIONS: This in vivo evaluation offers insights into the behavior of endocardial or epicardial PFA delivered using the lattice-tip catheter to normal or scarred porcine ventricular myocardium, thereby setting the stage for future clinical studies.

Chimerism as the basis for organ repair.

Organ and tissue repair are complex processes involving signaling molecules, growth factors, and cell cycle regulators that act in concert to promote cell division and differentiation at sites of injury. In embryonic development, progenitor fetal cells are actively involved in reparative mechanisms and display a biphasic interaction with the mother; and there is constant trafficking of fetal cells into maternal circulation and vice versa. This phenomenon of fetal microchimerism may have significant impact considering the primitive, multilineage nature of these cells. In published work, we have reported that fetal-derived placental cells expressing the homeodomain protein CDX2 retain all "stem" functional proteins of embryonic stem cells yet are endowed with additional functions in areas of growth, survival, homing, and immune modulation. These cells exhibit multipotency in vitro and in vivo, giving rise to spontaneously beating cardiomyocytes and vascular cells. In mouse models, CDX2 cells from female placentas can be administered intravenously to male mice subjected to myocardial infarction with subsequent homing of the CDX2 cells to infarcted areas and evidence of cellular regeneration with enhanced cardiac function. Elucidating the role of microchimeric fetal-derived placental cells may have broader scientific potential, as one can envision allogeneic cell therapy strategies targeted at tissue regeneration for a variety of organ systems.

Methodology and baseline characteristics of a randomized controlled trial testing a health care professional and peer-support program for patients with chronic obstructive pulmonary disease: The BREATHE2 study.

BACKGROUND: Self-management support (SMS) for patients with COPD can improve health-related quality of life (HRQOL). However, it remains unclear what SMS strategies are most effective. Using peer support to advance self-management is promising, as peer supporters possess credibility and can serve as role models. METHODS: We conducted a single-blinded RCT comparing the effectiveness of two strategies to support patients with COPD. The strategies were 'Health Care Professional (HCP)' and 'HCP Plus Peer' support. Peer support was provided by patients with COPD who have stopped smoking, completed an acute pulmonary rehabilitation program, and met the requirements for becoming a peer supporter. We enrolled patients receiving treatment at inpatient and outpatient settings. Patients were encouraged to invite one family-caregiver to enroll with them. The primary outcome measure was the change in HRQOL at 6 months post enrollment. Secondary outcomes included COPD-related and all-cause hospitalizations and ED visits. Caregiver outcomes included preparedness for caregiving, caregiver stress, and coping. RESULTS: A total of 292 patients as well as 50 family-caregivers were enrolled. The average patient age was 67.3 yrs. (SD 9.4), 61% were female and 26% were African-Americans. The majority of caregivers were females (68%) and were a spouse/partner (58%). DISCUSSION: This study tested a dual strategy for providing support to patients with COPD that incorporates peer and health care professional support. The study had minimal exclusion criteria. If shown effective, the study offers a program of peer support that can be readily implemented in health care settings.

Confounding effect of therapeutic protamine and heparin levels on routine and special coagulation testing.

: The management of a patient with hemophilia undergoing cardiovascular surgery relies on accurate coagulation test results. Both unfractionated heparin (UFH) and protamine sulfate used during cardiac surgery can interfere with factor and inhibitor assays. Here we describe the effects of UFH and protamine sulfate on routine coagulation, factor activity, and inhibitor assays. Pooled normal plasma (PNP) with UFH, PNP with protamine sulfate, PNP with both protamine sulfate and UFH were tested for the activated partial thromboplastin time (aPTT), prothrombin time (PT), thrombin time (TT), UFH anti-Xa, one-stage factor VIII (FVIII) activity, one-stage factor IX (FIX) activity, and Bethesda inhibitor assays for FVIII and FIX. UFH had a dose-dependent effect with TT, aPTT, and PT. On Bethesda inhibitor testing, FIX inhibition was detected at 1 U/ml UFH and 3 U/ml UFH for FVIII. Increasing protamine sulfate concentration in PNP prolonged the PT and aPTT in a dose-dependent manner, decreased FVIII and FIX activity and did not affect TT or UFH anti-Xa. At protamine sulfate doses of at least 200 µg/ml there was weak FVIII and FIX inhibition detected. At lower ratios of protamine sulfate to UFH (0.6 : 1-0.8 : 1), the aPTT decreased, suggesting reversal of UFH. However, at protamine sulfate to UFH ratios of 1.0 : 1 and higher, aPTT prolongation was observed. Inhibition of FVIII and FIX was detected at low ratios of protamine sulfate to UFH (below 0.4 : 1) and disappeared at higher ratios. UFH and protamine sulfate, alone or in combination, impact factor activity and inhibitor testing for both FVIII and FIX. Hence, factor activity and inhibitor assay results should be interpreted with caution when UFH or protamine sulfate are present.

Effect of a Hospital-Initiated Program Combining Transitional Care and Long-term Self-management Support on Outcomes of Patients Hospitalized With Chronic Obstructive Pulmonary Disease: A Randomized Clinical Trial.

Importance: Patients hospitalized for chronic obstructive pulmonary disease (COPD) exacerbations have high rehospitalization rates and reduced quality of life. Objective: To evaluate whether a hospital-initiated program that combined transition and long-term self-management support for patients hospitalized due to COPD and their family caregivers can improve outcomes. Design, Setting, and Participants: Single-site randomized clinical trial conducted in Baltimore, Maryland, with 240 participants. Participants were patients hospitalized due to COPD, randomized to intervention or usual care, and followed up for 6 months after hospital discharge. Enrollment occurred from March 2015 to May 2016; follow-up ended in December 2016. Interventions: The intervention (n = 120) involved a comprehensive 3-month program to help patients and their family caregivers with long-term self-management of COPD. It was delivered by nurses with special training on supporting patients with COPD using standardized tools. Usual care (n = 120) included transition support for 30 days after discharge to ensure adherence to discharge plan and connection to outpatient care. Main Outcomes and Measures: The primary outcome was number of COPD-related acute care events (hospitalizations and emergency department visits) per participant at 6 months. The co-primary outcome was change in participants' health-related quality of life measured by the St George's Respiratory Questionnaire (SGRQ) at 6 months after discharge (score, 0 [best] to 100 [worst]; 4-point difference is clinically meaningful). Results: Among 240 patients who were randomized (mean [SD] age, 64.9 [9.8] years; 61.7% women), 203 (85%) completed the study. The mean (SD) baseline SGRQ score was 62.3 (18.8) in the intervention group and 63.6 (17.4) in the usual care group. The mean number of COPD-related acute care events per participant at 6 months was 1.40 (95% CI, 1.01-1.79) in the intervention group vs 0.72 (95% CI, 0.45-0.97) in the usual care group (difference, 0.68 [95% CI, 0.22-1.15]; P = .004). The mean change in participants' SGRQ total score at 6 months was 2.81 in the intervention group and -2.69 in the usual care group (adjusted difference, 5.18 [95% CI, -2.15 to 12.51]; P = .11). During the study period, there were 15 deaths (intervention: 8; usual care: 7) and 339 hospitalizations (intervention: 202; usual care: 137). Conclusions and Relevance: In a single-site randomized clinical trial of patients hospitalized due to COPD, a 3-month program that combined transition and long-term self-management support resulted in significantly greater COPD-related hospitalizations and emergency department visits, without improvement in quality of life. Further research is needed to determine reasons for this unanticipated finding. Trial Registration: ClinicalTrials.gov Identifier: NCT02036294.

A regional massive hemorrhage protocol developed through a modified Delphi technique.

BACKGROUND: A massive hemorrhage protocol (MHP) enables rapid delivery of blood components in a patient who is exsanguinating pending definitive hemorrhage control, but there is variability in MHP implementation rates, content and compliance owing to challenges presented by infrequent activation, variable team performance and patient acuity. The goal of this project was to identify the key evidence-based principles and quality indicators required to develop a standardized regional MHP. METHODS: A modified Delphi consensus technique was performed in the spring and summer of 2018. Panellists used survey links to independently review and rate (on a 7-point Likert scale) 43 statements and 8 quality indicators drafted by a steering committee composed of transfusion medicine specialists and technologists, and trauma physicians. External stakeholder input from all hospitals in Ontario was sought. RESULTS: Three rounds were held with 36 experts from diverse clinical backgrounds. Consensus was reached for 42 statements and 8 quality indicators. Additional modifications from external stakeholders were incorporated to form the foundation for the proposed MHP. INTERPRETATION: This MHP template will provide the basis for the design of an MHP toolkit, including specific recommendations for pediatric and obstetrical patients, and for hospitals with limited availability of blood components or means to achieve definitive hemorrhage control. We believe that harmonization of MHPs in our region will simplify training, increase uptake of evidence-based interventions, enhance communication, improve patient comfort and safety, and, ultimately, improve patient outcomes.

Flow Cytometry and Cell Sorting Using Hematopoietic Progenitor Cells.

Flow cytometry is a widely used laser-based technology for rapid analysis of the expression of cell surface antigens and intracellular molecules in various cell types including hematopoietic stem/progenitor cells (HSPCs). Multiparametric analysis of individual cells within a short time frame makes this tool attractive and indispensable in the field of stem cell research. This is accomplished by harnessing the specific light scattering ability of the cell type, which determines its size and internal complexity. In addition, use of fluorescently conjugated antibodies allows the detection of a specific surface or intracellular antigen present at that particular stage. Fluorescent Activated Cell Sorting (FACS) is used to separate a subset of cells from a heterogeneous cell population based on fluorescent labeling. Here we describe the general principles of flow cytometry and detailed methods for the isolation of HSPCs using flow cytometry as a tool.

Multipotent fetal-derived Cdx2 cells from placenta regenerate the heart.

The extremely limited regenerative potential of adult mammalian hearts has prompted the need for novel cell-based therapies that can restore contractile function in heart disease. We have previously shown the regenerative potential of mixed fetal cells that were naturally found migrating to the injured maternal heart. Exploiting this intrinsic mechanism led to the current hypothesis that Caudal-type homeobox-2 (Cdx2) cells in placenta may represent a novel cell type for cardiac regeneration. Using a lineage-tracing strategy, we specifically labeled fetal-derived Cdx2 cells with enhanced green fluorescent protein (eGFP). Cdx2-eGFP cells from end-gestation placenta were assayed for cardiac differentiation in vitro and in vivo using a mouse model of myocardial infarction. We observed that these cells differentiated into spontaneously beating cardiomyocytes (CMs) and vascular cells in vitro, indicating multipotentiality. When administered via tail vein to infarcted wild-type male mice, they selectively and robustly homed to the heart and differentiated to CMs and blood vessels, resulting in significant improvement in contractility as noted by MRI. Proteomics and immune transcriptomics studies of Cdx2-eGFP cells compared with embryonic stem (ES) cells reveal that they appear to retain "stem"-related functions of ES cells but exhibit unique signatures supporting roles in homing and survival, with an ability to evade immune surveillance, which is critical for cell-based therapy. Cdx2-eGFP cells may potentially represent a therapeutic advance in allogeneic cell therapy for cardiac repair.

Exploring the effect of factor Xa inhibitors on rotational thromboelastometry: a case series of bleeding patients.

Direct oral anticoagulants (DOACs) have become the standard for thromboembolic risk management. In cases of major bleeding, trauma, or urgent surgery, accurate monitoring of DOAC activity is desirable; however, there is often no rapid, readily available test. We therefore explored the degree to which DOAC activity correlated with two coagulation assays: rotational thromboelastometry (ROTEM) and a standard coagulation assay in bleeding patients. We conducted a retrospective review of patients who experienced bleeding while on DOAC therapy from 2015 to 2017 at a Level 1 trauma center. ROTEM (EXTEM-clotting time {CT} in seconds), activated partial thromboplastin time (aPTT) (in seconds), prothrombin time (PT) (in seconds), DOAC specific drug test (anti-Xa and Hemoclot in ng/mL), and relevant clinical parameters were recorded. Descriptive statistics (median, range) and Spearman correlation coefficients were estimated. Differences between correlations were tested using Williams' t test. Twelve cases were reviewed (13 separate bleeding episodes). Sixteen measurements of DOAC activity, EXTEM-CT, and PT were obtained. The correlations with rivaroxaban activity were 0.96 and 0.86 (p = 0.2062) for PT and EXTEM-CT, respectively. The correlations with apixaban activity were 0.63 and 0.56 (p = 0.7175) for PT and EXTEM-CT, respectively. Analyses were not conducted for dabigatran due to limited data. Although not statistically significant, PT appears to have a higher correlation with direct Xa inhibitor activity than EXTEM-CT. Further research with larger samples is necessary to clarify the differences between ROTEM and standard assays in detecting DOAC activity.

Effect of a Program Combining Transitional Care and Long-term Self-management Support on Outcomes of Hospitalized Patients With Chronic Obstructive Pulmonary Disease: A Randomized Clinical Trial.

Importance: Patients hospitalized for chronic obstructive pulmonary disease (COPD) exacerbations have high rehospitalization rates and reduced quality of life. Objective: To evaluate a hospital-initiated program that combined transition and long-term self-management support for patients hospitalized due to COPD and their family caregivers. Design, Setting, and Participants: This single-site randomized clinical trial was conducted in Baltimore, Maryland, with 240 participants. Participants were patients hospitalized due to COPD, randomized to intervention or usual care, and followed up for 6 months after hospital discharge. Enrollment occurred from March 2015 to May 2016; follow-up ended in December 2016. Interventions: The intervention (n = 120) was a comprehensive 3-month program to help patients and their family caregivers with long-term self-management of COPD. It was delivered by COPD nurses (nurses with special training on supporting patients with COPD using standardized tools). Usual care (n = 120) included transition support for 30 days after discharge to ensure adherence to discharge plan and connection to outpatient care. Main Outcomes and Measures: The primary outcome was number of COPD-related acute care events (hospitalizations and emergency department visits) per participant at 6 months. The co-primary outcome was change in participants' health-related quality of life measured by the St George's Respiratory Questionnaire (SGRQ) at 6 months after discharge (score, 0 [best] to 100 [worst]; 4-point difference is clinically meaningful). Results: Among 240 patients who were randomized (mean [SD] age, 64.9 [9.8] years; females, 61.7%), 203 (85%) completed the study. The mean (SD) baseline SGRQ score was 63.1 (19.9) in the intervention group and 62.6 (19.3) in the usual care group. The mean number of COPD-related acute care events per participant at 6 months was 0.72 (95% CI, 0.45-0.97) in the intervention group vs 1.40 (95% CI, 1.01-1.79) in the usual care group (difference, 0.68 [95% CI, 0.22 to 1.15]; P = .004). The mean change in participants' SGRQ total score at 6 months was -1.53 in the intervention and +5.44 in the usual care group (adjusted difference, -6.69 [95% CI, -12.97 to -0.40]; P = .04). During the study period, there were 15 deaths (intervention: 7; usual care: 8) and 337 hospitalizations (intervention: 135; usual care: 202). Conclusions and Relevance: In a single-site randomized clinical trial of patients hospitalized due to COPD, a 3-month program that combined transition and long-term self-management support resulted in significantly fewer COPD-related hospitalizations and emergency department visits and better health-related quality of life at 6 months after discharge. Further research is needed to evaluate this intervention in other settings. Trial Registration: ClinicalTrials.gov Identifier: NCT02036294.