Lessons Learned from National Heart, Lung, and Blood Institute Covid-19 Clinical Trials.

AbstractIn response to the Covid-19 pandemic, the National Heart, Lung, and Blood Institute launched five multisite clinical trials testing candidate host tissue-directed medical interventions to hasten recovery, improve function, and reduce morbidity and mortality. Speed, flexibility, and collaboration were essential. This article from the Steering and Executive committees describes the Collaborating Network of Networks for Evaluating Covid-19 and Therapeutic Strategies (CONNECTS) research program that enrolled 6690 participants and evaluated 18 intervention strategies using 10 molecular agents across the care continuum (outpatient, inpatient, and post discharge), and reports lessons learned from this initiative.

Risk of Chronic Obstructive Pulmonary Disease and Receipt of a Breathing Test in 26 States and the District of Columbia, 2017-2018.

We estimated the prevalence of respiratory symptoms, chronic obstructive pulmonary disease (COPD) risk level, and receipt of a breathing test among adults without reported COPD in 26 states and the District of Columbia by using 2017-2018 Behavioral Risk Factor Surveillance System data. Among adults without reported COPD, the 3 respiratory symptoms indicating COPD (chronic cough, phlegm or mucus production, shortness of breath) were common (each >10%). About 15.

Update on RFA Increasing Use of Cardiac and Pulmonary Rehabilitation in Traditional and Community Settings NIH-Funded Trials: ADDRESSING CLINICAL TRIAL CHALLENGES PRESENTED BY THE COVID-19 PANDEMIC.

We previously described the design of six NIH-funded clinical trials designed to increase uptake and reduce disparities in the use of cardiac rehabilitation (CR) and pulmonary rehabilitation (PR) based on age, gender, race/ethnicity, and socioeconomic status. The onset of the COVID-19 global pandemic necessitated signifi cant revisions to the trials to ensure the safety of participants and research staff. This article described necessary modifi cations for assessments, interventions, and data collection to support a no-contact approach centered on the use of virtual/remote techniques that maintain both safety and the original intent and integrity of the trials.

Increasing Use of Cardiac and Pulmonary Rehabilitation in Traditional and Community Settings: OPPORTUNITIES TO REDUCE HEALTH CARE DISPARITIES.

Although both cardiac rehabilitation (CR) and pulmonary rehabilitation (PR) are recommended by clinical practice guidelines and covered by most insurers, they remain severely underutilized. To address this problem, the National Heart, Lung, and Blood Institute (NHLBI), in collaboration with the National Institute on Aging (NIA), developed Funding Opportunity Announcements (FOAs) in late 2017 to support phase II clinical trials to increase the uptake of CR and PR in traditional and community settings. The objectives of these FOAs were to (1) test strategies that will lead to increased use of CR and PR in the US population who are eligible based on clinical guidelines; (2) test strategies to reduce disparities in the use of CR and PR based on age, gender, race/ethnicity, and socioeconomic status; and (3) test whether increased use of CR and PR, whether by traditional center-based or new models, is accompanied by improvements in relevant clinical and patient-centered outcomes, including exercise capacity, cardiovascular and pulmonary risk factors, and quality of life.

Chronic Obstructive Pulmonary Disease and Smoking Status - United States, 2017.

Cigarette smoking is the leading cause of chronic obstructive pulmonary disease (COPD) in the United States; however, an estimated one fourth of adults with COPD have never smoked (1). CDC analyzed state-specific Behavioral Risk Factor Surveillance System (BRFSS) data from 2017, which indicated that, overall among U.S.

Female Sex and Gender in Lung/Sleep Health and Disease. Increased Understanding of Basic Biological, Pathophysiological, and Behavioral Mechanisms Leading to Better Health for Female Patients with Lung Disease.

Female sex/gender is an undercharacterized variable in studies related to lung development and disease. Notwithstanding, many aspects of lung and sleep biology and pathobiology are impacted by female sex and female reproductive transitions. These may manifest as differential gene expression or peculiar organ development.

Implementation Research to Address the United States Health Disadvantage: Report of a National Heart, Lung, and Blood Institute Workshop.

Four decades ago, U.S. life expectancy was within the same range as other high-income peer countries.

American Thoracic Society/National Heart, Lung, and Blood Institute Asthma-Chronic Obstructive Pulmonary Disease Overlap Workshop Report.

Asthma and chronic obstructive pulmonary disease (COPD) are highly prevalent chronic obstructive lung diseases with an associated high burden of disease. Asthma, which is often allergic in origin, frequently begins in infancy or childhood with variable airflow obstruction and intermittent wheezing, cough, and dyspnea. Patients with COPD, in contrast, are usually current or former smokers who present after the age of 40 years with symptoms (often persistent) including dyspnea and a productive cough.

Implementation Science to Accelerate Clean Cooking for Public Health.

Clean cooking has emerged as a major concern for global health and development because of the enormous burden of disease caused by traditional cookstoves and fires. The World Health Organization has developed new indoor air quality guidelines that few homes will be able to achieve without replacing traditional methods with modern clean cooking technologies, including fuels and stoves. However, decades of experience with improved stove programs indicate that the challenge of modernizing cooking in impoverished communities includes a complex, multi-sectoral set of problems that require implementation research.

Reducing Health Inequities in the U.S.: Recommendations From the NHLBI's Health Inequities Think Tank Meeting.

The National, Heart, Lung, and Blood Institute convened a Think Tank meeting to obtain insight and recommendations regarding the objectives and design of the next generation of research aimed at reducing health inequities in the United States. The panel recommended several specific actions, including: 1) embrace broad and inclusive research themes; 2) develop research platforms that optimize the ability to conduct informative and innovative research, and promote systems science approaches; 3) develop networks of collaborators and stakeholders, and launch transformative studies that can serve as benchmarks; 4) optimize the use of new data sources, platforms, and natural experiments; and 5) develop unique transdisciplinary training programs to build research capacity. Confronting health inequities will require engaging multiple disciplines and sectors (including communities), using systems science, and intervening through combinations of individual, family, provider, health system, and community-targeted approaches.

Perspectives from NHLBI Global Health Think Tank Meeting for Late Stage (T4) Translation Research.

Almost three-quarters (74%) of all the noncommunicable disease burden is found within low- and middle-income countries. In September 2014, the National Heart, Lung, and Blood Institute held a Global Health Think Tank meeting to obtain expert advice and recommendations for addressing compelling scientific questions for late stage (T4) research-research that studies implementation strategies for proven effective interventions-to inform and guide the National Heart, Lung, and Blood Institute's global health research and training efforts. Major themes emerged in two broad categories: 1) developing research capacity; and 2) efficiently defining compelling scientific questions within the local context.

The NHLBI SMARTT Program: A Novel Approach to Facilitate Translational Research for Heart, Lung and Blood Diseases.

The National Heart, Lung, and Blood Institute (NHLBI), one of the 27 Institutes/Centers within the National Institutes of Health (NIH), has a strong interest in promoting translational research. This interest can be traced to its mission statement, which reads in part: “The NHLBI stimulates basic discoveries about the causes of disease, enables the translation of basic discoveries into clinical practice, fosters training and mentoring of emerging scientists and physicians, and communicates research advances to the public.” (www.

Murine colitis is mediated by vimentin.

Vimentin, an abundant intermediate filament protein, presumably has an important role in stabilizing intracellular architecture, but its function is otherwise poorly understood. In a vimentin knockout (Vim KO) mouse model, we note that Vim KO mice challenged with intraperitoneal Escherichia coli control bacterial infection better than do wild-type (WT) mice. In vitro, Vim KO phagocytes show significantly increased capacity to mediate bacterial killing by abundant production of reactive oxygen species (ROS) and nitric oxides, likely due to interactions with the p47phox active subunit of NADPH oxidase.

OBSTRUCTIVE LUNG DISEASE AND EXPOSURE TO BURNING BIOMASS FUEL IN THE INDOOR ENVIRONMENT.

It is estimated that up to half of the world's population burns biomass fuel (wood, crop residues, animal dung and coal) for indoor uses such as cooking, lighting and heating. As a result, a large proportion of women and children are exposed to high levels of household air pollution (HAP). The short and long term effects of these exposures on the respiratory health of this population are not clearly understood.

Understanding the complexity of IgE-related phenotypes from childhood to young adulthood: a Mechanisms of the Development of Allergy (MeDALL) seminar.

Mechanisms of the Development of Allergy (MeDALL), a Seventh Framework Program European Union project, aims to generate novel knowledge on the mechanisms of initiation of allergy. Precise phenotypes of IgE-mediated allergic diseases will be defined in MeDALL. As part of MeDALL, a scientific seminar was held on January 24, 2011, to review current knowledge on the IgE-related phenotypes and to explore how a multidisciplinary effort could result in a new integrative translational approach.

Lung cancer and chronic obstructive pulmonary disease: needs and opportunities for integrated research.

Lung cancer and chronic obstructive pulmonary disease (COPD) are leading causes of morbidity and mortality in the United States and worldwide. They share a common environmental risk factor in cigarette smoke exposure and a genetic predisposition represented by the incidence of these diseases in only a fraction of smokers. The presence of COPD increases the risk of lung cancer up to 4.

The DEK nuclear autoantigen is a secreted chemotactic factor.

The nuclear DNA-binding protein DEK is an autoantigen that has been implicated in the regulation of transcription, chromatin architecture, and mRNA processing. We demonstrate here that DEK is actively secreted by macrophages and is also found in synovial fluid samples from patients with juvenile arthritis. Secretion of DEK is modulated by casein kinase 2, stimulated by interleukin-8, and inhibited by dexamethasone and cyclosporine A, consistent with a role as a proinflammatory molecule.

Conserved nontypeable Haemophilus influenzae-derived TLR2-binding lipopeptides synergize with IFN-beta to increase cytokine production by resident murine and human alveolar macrophages.

Nontypeable Haemophilus influenzae (NTHi) is strongly associated with exacerbations of chronic obstructive pulmonary disease, which often coincide with viral respiratory infections. TLR2 contributes importantly to innate immunity to NTHi, but whether this pathway is affected by simultaneous antiviral responses is unknown. To analyze potential interactions, resident murine and human alveolar macrophages (AMphi) were exposed, in the presence or absence of the appropriate rIFN-beta, to synthetic lipopeptides corresponding to the triacylated N-terminal fragments of three outer membrane proteins (OMP) (PCP, P4, and P6) that are highly conserved among different NTHi strains.

Specific engagement of TLR4 or TLR3 does not lead to IFN-beta-mediated innate signal amplification and STAT1 phosphorylation in resident murine alveolar macrophages.

The innate immune response must be mobilized promptly yet judiciously via TLRs to protect the lungs against pathogens. Stimulation of murine peritoneal macrophage (PMphi) TLR4 or TLR3 by pathogen-associated molecular patterns (PAMPs) typically induces type I IFN-beta, leading to autocrine activation of the transcription factor STAT1. Because it is unknown whether STAT1 plays a similar role in the lungs, we studied the response of resident alveolar macrophages (AMphi) or control PMphi from normal C57BL/6 mice to stimulation by PAMPs derived from viruses (polyriboinosinic:polyribocytidylic acid, specific for TLR3) or bacteria (Pam(3)Cys, specific for TLR2, and repurified LPS, specific for TLR4).