Supplemental Oxygen Therapy in Interstitial Lung Disease: A Narrative Review.

Patients with interstitial lung diseases (ILD) often have hypoxemia at rest and/or with exertion, for which supplemental oxygen is commonly prescribed. The number of patients with ILD who require supplemental oxygen is unknown, although estimates suggest it could be as much as 40%; many of these patients may require high-flow support (>4 L/min). Despite its frequent use, there is limited evidence for the impact of supplemental oxygen on clinical outcomes in ILD, with recommendations for its use primarily based on older studies in patients with chronic obstructive pulmonary disease. Oxygen use in ILD is rarely included as an outcome in clinical trials. Available evidence suggests that supplemental oxygen in ILD may improve quality of life and some exercise parameters in patients whose hypoxemia is a limiting factor; however, oxygen therapy also places new burdens and barriers on some patients that may counter its beneficial effects. The cost of supplemental oxygen in ILD is also unknown but likely represents a significant portion of overall healthcare costs in these patients. Current Centers for Medicare and Medicaid reimbursement policies provide only a modest increase in payment for high oxygen flows, which may negatively impact access to oxygen services and equipment for some patients with ILD. Future studies should examine clinical and quality-of-life outcomes for oxygen use in ILD. In the meantime, given the current limited evidence for supplemental oxygen and considering cost factors and other barriers, providers should take a patient-focused approach when considering supplemental oxygen prescriptions in patients with ILD.

PM2.5 and constituent component impacts on global DNA methylation in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease (ILD) whose outcomes are worsened with air pollution exposures. DNA methylation (DNAm) patterns are altered in lungs and blood from patients with IPF, but the relationship between air pollution exposures and DNAm patterns in IPF remains unexplored. This study aimed to evaluate the association of PM2.5 and constituent components with global DNAm in patients with IPF. Patients enrolled in either the University of Pittsburgh Simmons Center for ILD Registry (Simmons) or the U.S.-wide Pulmonary Fibrosis Foundation (PFF) Patient Registry with peripheral blood DNA samples were included. The averages of monthly exposures to PM2.5 and constituents over 1-year and 3-months pre-blood collection were matched to patient residential coordinates using satellite-derived hybrid models. Global DNAm percentage (%5 mC) was determined using the ELISA-based MethylFlash assay. Associations of pollutants with %5 mC were assessed using beta-regression, Cox models for mortality, and linear regression for baseline lung function. Mediation proportion was determined for models where pollutant-mortality and pollutant-%5 mC associations were significant. Inclusion criteria were met by 313 Simmons and 746 PFF patients with IPF. Higher PM2.5 3-month exposures prior to blood collection were associated with higher %5 mC in Simmons (ß = 0.02, 95%CI 0.0003-0.05, p = 0.047), with trends in the same direction in the 1-year period in both cohorts. Higher exposures to sulfate, nitrate, ammonium, and black carbon constituents were associated with higher %5 mC in multiple models. Percent 5 mC was not associated with IPF mortality or lung function, but was found to mediate between 2 and 5% of the associations of PM2.5, sulfate, and ammonium with mortality. In conclusion, we found that higher global DNAm is a novel biomarker for increased PM2.5 and anthropogenic constituent exposure in patients with IPF. Mechanistic research is needed to determine if DNAm has pathogenic relevance in mediating associations between pollutants and mortality in IPF.

Neighbourhood disadvantage impacts on pulmonary function in patients with sarcoidosis.

Background: This multicentre, international, prospective cohort study evaluated whether patients with pulmonary sarcoidosis living in neighbourhoods with greater material and social disadvantage experience worse clinical outcomes. Methods: The area deprivation index and the Canadian Index of Multiple Deprivation evaluate neighbourhood-level disadvantage in the US and Canada, with higher scores reflecting greater disadvantage. Multivariable linear regression evaluated associations of disadvantage with baseline forced vital capacity (FVC) or diffusing capacity of the lung for carbon monoxide (D LCO) and linear mixed effects models for associations with rate of FVC or D LCO decline, and competing hazards models were used for survival analyses in the US cohort, evaluating competing outcomes of death or lung transplantation. Adjustments were made for age at diagnosis, sex, race and smoking history. Results: We included 477 US and 122 Canadian patients with sarcoidosis. Higher disadvantage was not associated with survival or baseline FVC. The highest disadvantage quartile was associated with lower baseline D LCO in the US cohort (ß = -6.80, 95% CI -13.16 to -0.44, p=0.04), with similar findings in the Canadian cohort (ß = -7.47, 95% CI -20.28 to 5.33, p=0.25); with more rapid decline in FVC and D LCO in the US cohort (FVC ß = -0.40, 95% CI -0.70 to -0.11, p=0.007; D LCO ß = -0.59, 95% CI -0.95 to -0.23, p=0.001); and with more rapid FVC decline in the Canadian cohort (FVC ß = -0.80, 95% CI -1.37 to -0.24, p=0.003). Conclusion: Patients with sarcoidosis living in high disadvantage neighbourhoods experience worse baseline lung function and more rapid lung function decline, highlighting the need for better understanding of how neighbourhood-level factors impact individual patient outcomes.

Association of Particulate Matter Exposure With Lung Function and Mortality Among Patients With Fibrotic Interstitial Lung Disease.

Importance: Particulate matter 2.5 µm or less in diameter (PM2.5) is associated with adverse outcomes for patients with idiopathic pulmonary fibrosis, but its association with other fibrotic interstitial lung diseases (fILDs) and the association of PM2.5 composition with adverse outcomes remain unclear. Objective: To investigate the association of PM2.5 exposure with mortality and lung function among patients with fILD. Design, Setting, and Participants: In this multicenter, international, prospective cohort study, patients were enrolled in the Simmons Center for Interstitial Lung Disease Registry at the University of Pittsburgh in Pittsburgh, Pennsylvania; 42 sites of the Pulmonary Fibrosis Foundation Registry; and 8 sites of the Canadian Registry for Pulmonary Fibrosis. A total of 6683 patients with fILD were included (Simmons, 1424; Pulmonary Fibrosis Foundation, 1870; and Canadian Registry for Pulmonary Fibrosis, 3389). Data were analyzed from June 1, 2021, to August 2, 2022. Exposures: Exposure to PM2.5 and its constituents was estimated with hybrid models, combining satellite-derived aerosol optical depth with chemical transport models and ground-based PM2.5 measurements. Main Outcomes and Measures: Multivariable linear regression was used to test associations of exposures 5 years before enrollment with baseline forced vital capacity and diffusion capacity for carbon monoxide. Multivariable Cox models were used to test associations of exposure in the 5 years before censoring with mortality, and linear mixed models were used to test associations of exposure with a decrease in lung function. Multiconstituent analyses were performed with quantile-based g-computation. Cohort effect estimates were meta-analyzed. Models were adjusted for age, sex, smoking history, race, a socioeconomic variable, and site (only for Pulmonary Fibrosis Foundation and Canadian Registry for Pulmonary Fibrosis cohorts). Results: Median follow-up across the 3 cohorts was 2.9 years (IQR, 1.5-4.5 years), with death for 28% of patients and lung transplant for 10% of patients. Of the 6683 patients in the cohort, 3653 were men (55%), 205 were Black (3.1%), and 5609 were White (84.0%). Median (IQR) age at enrollment across all cohorts was 66 (58-73) years. A PM2.5 exposure of 8 µg/m3 or more was associated with a hazard ratio for mortality of 4.40 (95% CI, 3.51-5.51) in the Simmons cohort, 1.71 (95% CI, 1.32-2.21) in the Pulmonary Fibrosis Foundation cohort, and 1.45 (95% CI, 1.18-1.79) in the Canadian Registry for Pulmonary Fibrosis cohort. Increasing exposure to sulfate, nitrate, and ammonium PM2.5 constituents was associated with increased mortality across all cohorts, and multiconstituent models demonstrated that these constituents tended to be associated with the most adverse outcomes with regard to mortality and baseline lung function. Meta-analyses revealed consistent associations of exposure to sulfate and ammonium with mortality and with the rate of decrease in forced vital capacity and diffusion capacity of carbon monoxide and an association of increasing levels of PM2.5 multiconstituent mixture with all outcomes. Conclusions and Relevance: This cohort study found that exposure to PM2.5 was associated with baseline severity, disease progression, and mortality among patients with fILD and that sulfate, ammonium, and nitrate constituents were associated with the most harm, highlighting the need for reductions in human-derived sources of pollution.

Palliative Care Early in the Care Continuum among Patients with Serious Respiratory Illness: An Official ATS/AAHPM/HPNA/SWHPN Policy Statement.

Background: Patients with serious respiratory illness and their caregivers suffer considerable burdens, and palliative care is a fundamental right for anyone who needs it. However, the overwhelming majority of patients do not receive timely palliative care before the end of life, despite robust evidence for improved outcomes. Goals: This policy statement by the American Thoracic Society (ATS) and partnering societies advocates for improved integration of high-quality palliative care early in the care continuum for patients with serious respiratory illness and their caregivers and provides clinicians and policymakers with a framework to accomplish this. Methods: An international and interprofessional expert committee, including patients and caregivers, achieved consensus across a diverse working group representing pulmonary-critical care, palliative care, bioethics, health law and policy, geriatrics, nursing, physiotherapy, social work, pharmacy, patient advocacy, psychology, and sociology. Results: The committee developed fundamental values, principles, and policy recommendations for integrating palliative care in serious respiratory illness care across seven domains: 1) delivery models, 2) comprehensive symptom assessment and management, 3) advance care planning and goals of care discussions, 4) caregiver support, 5) health disparities, 6) mass casualty events and emergency preparedness, and 7) research priorities. The recommendations encourage timely integration of palliative care, promote innovative primary and secondary or specialist palliative care delivery models, and advocate for research and policy initiatives to improve the availability and quality of palliative care for patients and their caregivers. Conclusions: This multisociety policy statement establishes a framework for early palliative care in serious respiratory illness and provides guidance for pulmonary-critical care clinicians and policymakers for its proactive integration.

The Role of Palliative Care in COPD.

COPD is the fourth leading cause of death in the United States and is a serious respiratory illness characterized by years of progressively debilitating breathlessness, high prevalence of associated depression and anxiety, frequent hospitalizations, and diminished well-being. Despite the potential to confer significant quality-of-life benefits for patients and their care partners and to improve end-of-life (EOL) care, specialist palliative care is rarely implemented in COPD, and when initiated, it often occurs only at the very EOL. Primary palliative care delivered by frontline clinicians is a feasible model, but is not integrated routinely in COPD. In this review, we discuss the following: (1) the role of specialist and primary palliative care for patients with COPD and the case for earlier integration into routine practice; (2) the domains of the National Consensus Project Guidelines for Quality Palliative Care applied to people living with COPD and their care partners; and (3) triggers for initiating palliative care and practical ways to implement palliative care using case-based examples. This review solidifies that palliative care is much more than hospice and EOL care and demonstrates that early palliative care is appropriate at any point during the COPD trajectory. We emphasize that palliative care should be integrated long before the EOL to provide comprehensive support for patients and their care partners and to prepare them better for the EOL.

Neighborhood-Level Disadvantage Impacts on Patients with Fibrotic Interstitial Lung Disease.

Rationale: Fibrotic interstitial lung disease (fILD) is a group of pathologic entities characterized by scarring of the lungs and high morbidity and mortality. Research investigating how socioeconomic and residential factors impact outcomes in patients with fILD is lacking. Objectives: To determine the association between neighborhood-level disadvantage and presentation severity, disease progression, lung transplantation, and mortality in patients with fILD from the United States and Canada. Methods: We performed a multicenter, international, prospective cohort study of 4,729 patients with fILD from one U.S. and eight Canadian ILD registry sites. Neighborhood-level disadvantage was measured by the area deprivation index in the United States and the Canadian Index of Multiple Deprivation in Canada. Measurements and Main Results: In the U.S. but not in the Canadian cohort, patients with fILD living in neighborhoods with the greatest disadvantage (top quartile) experience the highest risk of mortality (hazard ratio = 1.51, P = 0.002), and in subgroups of patients with idiopathic pulmonary fibrosis, the top quartile of disadvantage experienced the lowest odds of lung transplantation (odds ratio = 0.46, P = 0.04). Greater disadvantage was associated with reduced baseline DLCO in both cohorts, but it was not associated with baseline FVC or FVC or DLCO decline in either cohort. Conclusions: Patients with fILD who live in areas with greater neighborhood-level disadvantage in the United States experience higher mortality, and patients with idiopathic pulmonary fibrosis experience lower odds of lung transplantation. These disparities are not seen in Canadian patients, which may indicate differences in access to care between the United States and Canada.

Lung transplantation for idiopathic pulmonary fibrosis enriches for individuals with telomere-mediated disease.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most common indication for lung transplantation in North America and variants in telomere-maintenance genes are the most common identifiable cause of IPF. We reasoned that younger IPF patients are more likely to undergo lung transplantation and we hypothesized that lung transplant recipients would be enriched for individuals with telomere-mediated disease due to the earlier onset and more severe disease in these patients. METHODS: Individuals with IPF who underwent lung transplantation or were evaluated in an interstitial lung disease specialty clinic who did not undergo lung transplantation were examined. Genetic evaluation was completed via whole genome sequencing (WGS) of 426 individuals and targeted sequencing for 5 individuals. Rare variants in genes previously associated with IPF were classified using the American College of Medical Genetics guidelines. Telomere length from WGS data was measured using TelSeq software. Patient characteristics were collected via medical record review. RESULTS: Of 431 individuals, 149 underwent lung transplantation for IPF. The median age of diagnosis of transplanted vs non-transplanted individuals was significantly younger (60 years vs 70 years, respectively, p<0.0001). IPF lung transplant recipients (IPF-LTRs) were twice as likely to have telomere-related rare variants compared to non-transplanted individuals (24% vs 12%, respectively, p=0.0013). IPF-LTRs had shorter telomeres than non-transplanted IPF patients (p=0.0028) and >85% had telomeres below the age-adjusted mean. Post-transplant survival and CLAD were similar amongst IPF-LTRs with rare variants in telomere-maintenance genes compared to those without, as well as in those with short telomeres versus longer telomeres. CONCLUSIONS: There is an enrichment for telomere-maintenance gene variants and short telomeres among IPF-LTRs. However, transplant outcomes of survival and CLAD do not differ by gene variants or telomere length within IPF-LTRs. Our findings support individual with telomere-mediated disease should not be excluded from lung transplantation and focusing research efforts on therapies directed toward individuals with short-telomere mediated disease.

Patient-centered Outcomes Research in Interstitial Lung Disease: An Official American Thoracic Society Research Statement.

Background: In the past two decades, many advances have been made to our understanding of interstitial lung disease (ILD) and the way we approach its treatment. Despite this, many questions remain unanswered, particularly those related to how the disease and its therapies impact outcomes that are most important to patients. There is currently a lack of guidance on how to best define and incorporate these patient-centered outcomes in ILD research. Objectives: To summarize the current state of patient-centered outcomes research in ILD, identify gaps in knowledge and research, and highlight opportunities and methods for future patient-centered research agendas in ILD. Methods: An international interdisciplinary group of experts was assembled. The group identified top patient-centered outcomes in ILD, reviewed available literature for each outcome, highlighted important discoveries and knowledge gaps, and formulated research recommendations. Results: The committee identified seven themes around patient-centered outcomes as the focus of the statement. After a review of the literature and expert committee discussion, we developed 28 research recommendations. Conclusions: Patient-centered outcomes are key to ascertaining whether and how ILD and interventions used to treat it affect the way patients feel and function in their daily lives. Ample opportunities exist to conduct additional work dedicated to elevating and incorporating patient-centered outcomes in ILD research.

The Role of Palliative Care in Reducing Symptoms and Improving Quality of Life for Patients with Idiopathic Pulmonary Fibrosis: A Review.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with a median survival of 3-4 years from time of initial diagnosis, similar to the time course of many malignancies. A hallmark of IPF is its unpredictable disease course, ranging from long periods of clinical stability to acute exacerbations with rapid decompensation. As the disease progresses, patients with chronic cough and progressive exertional dyspnea become oxygen dependent. They may experience significant distress due to concurrent depression, anxiety, and fatigue, which often lead to increased symptom burden and decreased quality of life. Despite these complications, palliative care is an underutilized, and often underappreciated, resource before end-of-life care in this population. While there is growing recognition about early palliative care in IPF, current data suggest referral patterns vary widely based on institutional practices. In addition to focusing on symptom management, there is emphasis on supplemental oxygen use, pulmonary rehabilitation, quality of life, and end-of-life care. Importantly, increased use of support groups and national foundation forums have served as venues for further disease education, communication, and advanced care planning outside of the hospital settings. The purpose of this review article is to discuss the clinical features of IPF, the role of palliative care in chronic disease management, current data supporting benefits of palliative care in IPF, its role in symptom management, and practices to help patients and their caregivers achieve their best quality of life.

Assessing Patterns of Palliative Care Referral and Location of Death in Patients with Idiopathic Pulmonary Fibrosis: A Sixteen-Year Single-Center Retrospective Cohort Study.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with an unpredictable course and a median survival of three to four years. This timeline challenges providers to approach diagnosis, oxygen therapy, rehabilitation, transplantation, and end-of-life discussions in limited encounters. There is currently no widely accepted guideline for determining when IPF patients should be referred to palliative care (PC). Objective: We sought to describe the patient and clinical factors associated with PC referral, as well as its impact on mortality and location of death. We also aimed to examine temporal trends in PC referral in this population. Materials and Methods: Patient data were retrospectively extracted from the health system repository of our specialty referral center for all new IPF patients evaluated between 2000 and 2016 (n = 828). Exclusion criteria included transplant recipients and patients who did not have IPF. Results: One hundred twelve (13.5%) IPF patients received formal PC referral. Recipients were older at diagnosis (72 years vs. 69 years, p < 0.001), had higher frequency of Charlson Comorbidity Index ≥1 (55% vs. 42%, p = 0.011), resided closer to our institution (16 miles vs. 54 miles, p < 0.001), and had a higher number of total outpatient visits (7 vs. 4, p < 0.001). PC was associated with less in-hospital death (44% vs. 60%, p = 0.006) and more in-home and hospice death (56% vs. 40%, p = 0.006). Conclusions: IPF patients referred to PC were older with more severe comorbidities, resided closer to our specialty referral center, and had more outpatient follow-up. This was associated with more in-home and hospice deaths. The patient-provider relationship and frequency of follow-up visits likely play important roles in the introduction of end-of-life discussions.

Optimizing Home Oxygen Therapy. An Official American Thoracic Society Workshop Report.

More than 1.5 million adults in the United States use supplemental oxygen for a variety of respiratory disorders to improve their quality of life and prolong survival. This document describes recommendations from a multidisciplinary workshop convened at the ATS International Conference in 2017 with the goal of optimizing home oxygen therapy for adults. Ideal supplemental oxygen therapy is patient-specific, provided by a qualified clinician, includes an individualized prescription and therapeutic education program, and offers oxygen systems that are safe, promote mobility, and treat hypoxemia. Recently, patients and clinicians report a growing number of problems with home oxygen in the United States. Oxygen users experience significant functional, mechanical, and financial problems and a lack of education related to their oxygen equipment-problems that impact their quality of life. Health care providers report a lack of readily accessible resources needed to prescribe oxygen systems correctly and efficiently. Patients with certain lung diseases are affected more than others because of physically unmanageable or inadequate portable systems. Analysis is needed to quantify the unintended impact that the Centers for Medicare and Medicaid Services Competitive Bidding Program has had on patients receiving supplemental oxygen from durable medical equipment providers. Studies using effectiveness and implementation research designs are needed to develop and evaluate new models for patient education, identify effective ways for stakeholders to interface, determine the economic benefit of having respiratory therapists perform in-home education and follow-up testing, and collaborate with technology companies to improve portable oxygen devices. Generation of additional evidence of the benefit of supplemental oxygen across the spectrum of advanced lung diseases and the development of clinical practice guidelines should both be prioritized.

Patient Perceptions of the Adequacy of Supplemental Oxygen Therapy. Results of the American Thoracic Society Nursing Assembly Oxygen Working Group Survey.

RATIONALE: Pulmonary clinicians and patients anecdotally report barriers to home supplemental oxygen services including inadequate supply, unacceptable portable options, and equipment malfunction. Limited evidence exists to describe or quantify these problems. OBJECTIVES: To describe the frequency and type of problems experienced by supplemental oxygen users in the United States. METHODS: The Patient Supplemental Oxygen Survey, a self-report questionnaire, was posted on the American Thoracic Society Public Advisory Roundtable and patient and health care-affiliated websites. Respondents were invited to complete the questionnaire, using targeted e-mail notifications. Data were analyzed using descriptive statistics, paired t tests, and χ2 analysis. RESULTS: In total, 1,926 responses were analyzed. Most respondents reported using oxygen 24 h/d, for 1-5 years, and 31% used high flow with exertion. Oxygen use varied, with only 29% adjusting flow rates based on oximeter readings. The majority (65%) reported not having their oxygen saturation checked when equipment was delivered. Sources of instruction included the delivery person (64%), clinician (8%), and no instruction (10%). Approximately one-third reported feeling "very" or "somewhat" unprepared to operate their equipment. Fifty-one percent of the patients reported oxygen problems, with the most frequent being equipment malfunction, lack of physically manageable portable systems, and lack of portable systems with high flow rates. Most respondents identified multiple problems (average, 3.6 ± 2.3; range, 1-12) in addition to limitations in activities outside the home because of inadequate portable oxygen systems (44%). Patients living in Competitive Bidding Program areas reported oxygen problems more often than those who did not (55% [389] vs. 45% [318]; P = 0.025). Differences in sample characteristics and oxygen problems were noted across diagnostic categories, with younger, dyspneic, high-flow users, and respondents who did not receive oxygen education, relating more oxygen problems. Respondents reporting oxygen problems also experienced increased health care resource utilization. CONCLUSIONS: Supplemental oxygen users experience frequent and varied problems, particularly a lack of access to effective instruction and adequate portable systems. Initiatives by professional and patient organizations are needed to improve patient education, and to promote access to equipment and services tailored to each patient's needs.

Validation of a 52-gene risk profile for outcome prediction in patients with idiopathic pulmonary fibrosis: an international, multicentre, cohort study.

BACKGROUND: The clinical course of idiopathic pulmonary fibrosis (IPF) is unpredictable. Clinical prediction tools are not accurate enough to predict disease outcomes. METHODS: We enrolled patients with IPF diagnosis in a six-cohort study at Yale University (New Haven, CT, USA), Imperial College London (London, UK), University of Chicago (Chicago, IL, USA), University of Pittsburgh (Pittsburgh, PA, USA), University of Freiburg (Freiburg im Breisgau, Germany), and Brigham and Women's Hospital-Harvard Medical School (Boston, MA, USA). Peripheral blood mononuclear cells or whole blood were collected at baseline from 425 participants and from 98 patients (23%) during 4-6 years' follow-up. A 52-gene signature was measured by the nCounter analysis system in four cohorts and extracted from microarray data (GeneChip) in the other two. We used the Scoring Algorithm for Molecular Subphenotypes (SAMS) to classify patients into low-risk or high-risk groups based on the 52-gene signature. We studied mortality with a competing risk model and transplant-free survival with a Cox proportional hazards model. We analysed timecourse data and response to antifibrotic drugs with linear mixed effect models. FINDINGS: The application of SAMS to the 52-gene signature identified two groups of patients with IPF (low-risk and high-risk), with significant differences in mortality or transplant-free survival in each of the six cohorts (hazard ratio [HR] range 2·03-4·37). Pooled data showed similar results for mortality (HR 2·18, 95% CI 1·53-3·09; p<0·0001) or transplant-free survival (2·04, 1·52-2·74; p<0·0001). Adding 52-gene risk profiles to the Gender, Age, and Physiology index significantly improved its mortality predictive accuracy. Temporal changes in SAMS scores were associated with changes in forced vital capacity (FVC) in two cohorts. Untreated patients did not shift their risk profile over time. A simultaneous increase in up score and decrease in down score was predictive of decreased transplant-free survival (3·18, 1·16-8·76; p=0·025) in the Pittsburgh cohort. A simultaneous decrease in up score and increase in down score after initiation of antifibrotic drugs was associated with a significant (p=0·0050) improvement in FVC in the Yale cohort. INTERPRETATION: The peripheral blood 52-gene expression signature is predictive of outcome in patients with IPF. The potential value of the 52-gene signature in predicting response to therapy should be determined in prospective studies. FUNDING: The Pulmonary Fibrosis Foundation, the Harold Amos Medical Faculty Development Program of the Robert Wood Johnson Foundation, and the National Heart, Lung, and Blood Institute of the US National Institutes of Health.