NIH Workshop Research Articles

Detection of Bronchiolitis Obliterans Syndrome after Pediatric Hematopoietic Stem Cell Transplantation: An Official American Thoracic Society Clinical Practice Guideline.

Background: Many children undergo allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of malignant and nonmalignant conditions. Unfortunately, pulmonary complications occur frequently post-HSCT, with bronchiolitis obliterans syndrome (BOS) being the most common noninfectious pulmonary complication. Current international guidelines contain conflicting recommendations regarding post-HSCT surveillance for BOS, and a recent NIH workshop highlighted the need for a standardized approach to post-HSCT monitoring. As such, this guideline provides an evidence-based approach to detection of post-HSCT BOS in children. Methods: A multinational, multidisciplinary panel of experts identified six questions regarding surveillance for, and evaluation of, post-HSCT BOS in children. A systematic review of the literature was undertaken to answer each question. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to rate the quality of evidence and the strength of recommendations. Results: The panel members considered the strength of each recommendation and evaluated the benefits and risks of applying the intervention. In formulating the recommendations, the panel considered patient and caregiver values, the cost of care, and feasibility. Recommendations addressing the role of screening pulmonary function testing and diagnostic tests in children with suspected post-HSCT BOS were made. Following a Delphi process, new diagnostic criteria for pediatric post-HSCT BOS were also proposed. Conclusions: This document provides an evidence-based approach to the detection of post-HSCT BOS in children while also highlighting considerations for the implementation of each recommendation. Further, the document describes important areas for future research.

The emerging importance of lymphatics in health and disease: an NIH workshop report.

The lymphatic system (LS) is composed of lymphoid organs and a network of vessels that transport interstitial fluid, antigens, lipids, cholesterol, immune cells, and other materials in the body. Abnormal development or malfunction of the LS has been shown to play a key role in the pathophysiology of many disease states. Thus, improved understanding of the anatomical and molecular characteristics of the LS may provide approaches for disease prevention or treatment. Recent advances harnessing single-cell technologies, clinical imaging, discovery of biomarkers, and computational tools have led to the development of strategies to study the LS. This Review summarizes the outcomes of the NIH workshop entitled "Yet to be Charted: Lymphatic System in Health and Disease," held in September 2022, with emphasis on major areas for advancement. International experts showcased the current state of knowledge regarding the LS and highlighted remaining challenges and opportunities to advance the field.

The Obesity Society is turning 40: A history of the early years.

The North American Association for the Study of Obesity (NAASO), the precursor of The Obesity Society (TOS), was founded in 1981 and turns 40 years old in 2021. The Society was organized by George Bray along with John Brunzell, C. Wayne Callaway, M.R.C. Greenwood, and Judith Stern. It held its foundational meeting with a theme of "Types of Obesity: Animal Models and Clinical Applications" at Vassar College in the fall of 1982 along with symposia and an NIH workshop titled "Methods of Characterizing Human Obesity." At a follow-up meeting during the Fourth International Congress on Obesity, Barbara Hansen was elected President, Judith Stern Secretary, and Anne Sullivan Treasurer. Incorporation of NAASO occurred in 1984.

Association between Intermittent Hypoxemia and Severe Bronchopulmonary Dysplasia in Preterm Infants.

Rationale: Bronchopulmonary dysplasia increases the risk of disability in extremely preterm infants. Although the pathophysiology remains uncertain, prior exposure to intermittent hypoxemia may play a role in this relationship. Objectives: To determine the association between prolonged episodes of intermittent hypoxemia and severe bronchopulmonary dysplasia. Methods: A post hoc analysis of extremely preterm infants in the Canadian Oxygen Trial who survived to 36 weeks' postmenstrual age was performed. Oxygen saturations <80% for ⩾1 minute and the proportion of time per day with hypoxemia were quantified using continuous pulse oximetry data that had been sampled every 10 seconds from within 24 hours of birth until 36 weeks' postmenstrual age. The study outcome was severe bronchopulmonary dysplasia as defined in the 2001 NIH Workshop Summary. Measurements and Main Results: Of 1,018 infants, 332 (32.6%) developed severe bronchopulmonary dysplasia. The median number of hypoxemic episodes ranged from 0.8/day (interquartile range, 0.2-1.1) to 60.2/day (interquartile range, 51.4-70.3) among the least and most affected 10% of infants. Compared with the lowest decile of exposure to hypoxemic episodes, the adjusted relative risk of severe bronchopulmonary dysplasia increased progressively from 1.72 (95% confidence interval, 1.55-1.90) at the 2nd decile to 20.40 (95% confidence interval, 12.88-32.32) at the 10th decile. Similar risk gradients were observed for time in hypoxemia. Significant differences in the rates of hypoxemia between infants with and without severe bronchopulmonary dysplasia emerged within the first week after birth. Conclusions: Prolonged intermittent hypoxemia beginning in the first week after birth was associated with an increased risk of developing severe bronchopulmonary dysplasia among extremely preterm infants. Clinical trial registered with www.isrctn.com (ISRCTN62491227) and www.clinicaltrials.gov (NCT00637169).

Advancing long-acting and extended delivery HIV prevention and treatment regimens through behavioural science: NIH workshop directions.

Advancing long-acting and extended delivery HIV prevention and treatment regimens through behavioural science: NIH workshop directions.

NIH Workshop on HIV-Associated Comorbidities, Coinfections, and Complications: Summary and Recommendation for Future Research.

With potent antiretroviral therapy and simplified regimens, people living with HIV (PWH) are achieving near-normal lifespans but not necessarily a normal health span or healthy aging. PWH have a higher than expected risk of developing a number of non-AIDS comorbidities, coinfections, and complications (CCC), often against a background of stigma, poverty, and isolation. To gain a better understanding of research needs for HIV-associated CCC, the NIH convened a 2-day workshop (HIV-associated CCC, or HIV ACTION). A cross-institute NIH planning committee identified 6 key research areas: epidemiology and population research, pathogenesis and basic science research, clinical research, implementation science research, syndemics research and international research in low and middle income countries. Investigators were selected to lead working groups (WGs) to assess the state-of-the-art and identify 3-5 priority areas in each field before the workshop. A 2-day program at the NIH was developed which included presentations by invited experts and WG members. Over 400 participants attended the workshop. After general and individual WG discussions, the most pressing gaps, questions, or proposed action items were identified. Priority lists of pressing research issues were presented by cochairs of each WG. A detailed report is posted at the NHLBI website. This article reports the streamlined priority list and a summary of WG discussions to inform investigators of current priorities in the field. Collaborative efforts of many disciplines are needed to improve the health and wellbeing of PWH. Several common themes emerged across WG representing potential priorities for investigators and recommendations for the NIH.

NIH Workshop Report: sensory nutrition and disease

In November 2019, the NIH held the “Sensory Nutrition and Disease” workshop to challenge multidisciplinary researchers working at the interface of sensory science, food science, psychology, neuroscience, nutrition, and health sciences to explore how chemosensation influences dietary choice and health. This report summarizes deliberations of the workshop, as well as follow-up discussion in the wake of the current pandemic. Three topics were addressed: A) the need to optimize human chemosensory testing and assessment, B) the plasticity of chemosensory systems, and C) the interplay of chemosensory signals, cognitive signals, dietary intake, and metabolism. Several ways to advance sensory nutrition research emerged from the workshop: 1) refining methods to measure chemosensation in large cohort studies and validating measures that reflect perception of complex chemosensations relevant to dietary choice; 2) characterizing interindividual differences in chemosensory function and how they affect ingestive behaviors, health, and disease risk; 3) defining circuit-level organization and function that link and interact with gustatory, olfactory, homeostatic, visceral, and cognitive systems; and 4) discovering new ligands for chemosensory receptors (e.g., those produced by the microbiome) and cataloging cell types expressing these receptors. Several of these priorities were made more urgent by the current pandemic because infection with sudden acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the ensuing coronavirus disease of 2019 has direct short- and perhaps long-term effects on flavor perception. There is increasing evidence of functional interactions between the chemosensory and nutritional sciences. Better characterization of this interface is expected to yield insights to promote health, mitigate disease risk, and guide nutrition policy.

NIH Workshop 2018: Towards Minimally Invasive or Noninvasive Approaches to Assess Tissue Oxygenation Pre- and Post-transfusion.

NIH Workshop 2018: Towards Minimally Invasive or Noninvasive Approaches to Assess Tissue Oxygenation Pre- and Post-transfusion.

Abstract PO-262: Achieving health equity in cancer preventive services: NIH Workshop insights on barriers and the effectiveness of evidence-based interventions and strategies

Abstract Background: Evidence-based guidelines for preventive services are developed by expert groups such as the U.S. Preventive Services Task Force (USPSTF) to help Americans stay healthy. Despite the proven value of evidence-based preventive services (e.g., screenings, provider counseling, and preventive medications), implementation by providers and uptake by patients vary, contributing to disparities in disease burden and life expectancy. The NIH convened a workshop with multidisciplinary and multisector participants in June 2019 to assess the available scientific evidence on achieving health equity in the use of clinical preventive services for three leading causes of death: diabetes, heart disease, and cancer. Methods: The workshop was framed around five key questions (KQ) and included a systematic evidence review, speaker presentations, and public discussion. KQ 1-2 considered the effects of barriers on the part of providers and patients to adopting and implementing evidence-based preventive services, and how they contribute to health disparities. KQ 3-5 addressed the effectiveness of health information technology and health care organization interventions to reduce disparities in preventive services use. An unbiased, independent panel of experts considered the scientific evidence in addition to speaker and audience perspectives to develop a report of findings and recommendations for addressing disparities in the use of ten clinical preventive services recommended by the USPSTF. Results: Overall, the need for more research on the effects of barriers was identified. However, compared with heart disease and diabetes, the barriers to adopting preventive services for breast, cervical, and colorectal cancer screening have received greater attention. While patient navigation was shown to be effective in increasing cancer screening rates, strategies for bundling preventive services and implementing health information technologies require more study. The importance of addressing unmet basic needs related to health and enhancing community resources to reduce disparities were recurring themes throughout the workshop. Lastly, there were implications for more research in cancer dissemination and implementation. Conclusion: Chronic diseases, including heart disease, cancer, and diabetes, are responsible for seven of every ten deaths in the U.S. each year. Greater use of proven clinical preventive services could avert the loss of millions of life-years. Achieving health equity in preventive services is feasible, but requires efforts at the patient, provider, healthcare organization, and community levels, and greater attention to addressing social determinants of health. Citation Format: Antoinette Percy-Laurry, Richard Berzon, Jennifer Croswell, Carrie Klabunde, Melissa Green Parker, LeShawndra Price, Pamela Thornton, Kate Winseck, Xinzhi Zhang. Achieving health equity in cancer preventive services: NIH Workshop insights on barriers and the effectiveness of evidence-based interventions and strategies [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-262.

Knowledge gaps in understanding the metabolic and clinical effects of excess folates/folic acid: a summary, and perspectives, from an NIH workshop

Folate, an essential nutrient found naturally in foods in a reduced form, is present in dietary supplements and fortified foods in an oxidized synthetic form (folic acid). There is widespread agreement that maintaining adequate folate status is critical to prevent diseases due to folate inadequacy (e.g., anemia, birth defects, and cancer). However, there are concerns of potential adverse effects of excess folic acid intake and/or elevated folate status, with the original concern focused on exacerbation of clinical effects of vitamin B-12 deficiency and its role in neurocognitive health. More recently, animal and observational studies have suggested potential adverse effects on cancer risk, birth outcomes, and other diseases. Observations indicating adverse effects from excess folic acid intake, elevated folate status, and unmetabolized folic acid (UMFA) remain inconclusive; the data do not provide the evidence needed to affect public health recommendations. Moreover, strong biological and mechanistic premises connecting elevated folic acid intake, UMFA, and/or high folate status to adverse health outcomes are lacking. However, the body of evidence on potential adverse health outcomes indicates the need for comprehensive research to clarify these issues and bridge knowledge gaps. Three key research questions encompass the additional research needed to establish whether high folic acid or total folate intake contributes to disease risk. 1) Does UMFA affect biological pathways leading to adverse health effects? 2) Does elevated folate status resulting from any form of folate intake affect vitamin B-12 function and its roles in sustaining health? 3) Does elevated folate intake, regardless of form, affect biological pathways leading to adverse health effects other than those linked to vitamin B-12 function? This article summarizes the proceedings of an August 2019 NIH expert workshop focused on addressing these research areas.

Working toward precision medicine approaches to treat severe obesity in adolescents: report of an NIH workshop

This paper presents the results of a multidisciplinary expert workshop to identify current knowledge and more importantly current gaps in knowledge on the epidemiological and biopsychosocial determinants of obesity and its optimal treatment approaches.

Research Recommendations From the National Institutes of Health Workshop on Predicting, Preventing, and Treating Preeclampsia

Preeclampsia (PE) is a pregnancy-specific, multisystemic disorder that occurs in roughly 5% of pregnancies in the United States.1,2 The rates of PE in the United States have been steadily rising over the past 30 years with PE being a leading cause of maternal and fetal/neonatal morbidity and mortality.3 Women with PE, as well as their offspring, are at greater risk for chronic diseases, including cardiovascular disease (CVD) later in life.4,5 Despite being the leading cause of maternal death and a major contributor to maternal and perinatal morbidity, drug treatment to prevent PE is at best minimally effective, and current management therapies have significant limitations. In fact, at present, delivery is considered the only effective intervention for treating PE6 and even then PE may continue in the postpartum period or present de novo.7 The lack of progress in identifying new therapeutic targets for the treatment of PE is due in part to a paucity of animal models that address the heterogeneity of human PE as well as lack of understanding of basic disease mechanisms. There are no models of spontaneously developing PE in animals. Developing novel animal models to mimic human PE, identifying biomarkers to predict PE, conducting basic studies to better understand disease mechanisms, and ultimately, developing novel therapeutic strategies are clearly needed. The National Heart, Lung, and Blood Institute (NHLBI), in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), held a workshop to examine the topic of Predicting, Preventing and Treating Preeclampsia on May 21–22, 2018, in Bethesda, MD. Speakers were chosen for expertise in general areas identified as important and cutting edge by the organizers. Specific topics discussed during the workshop were: i) pathophysiology of PE; ii) immunological origins of PE; iii) how to define subsets of PE; iv) biomarkers; v) nutritional factors; vi) genetics and epigenetics; vii) animal models; viii) collaboration, harmonization, sharing large data and samples sets in the study of PE; ix) periconceptional contributors to pathophysiology; x) clinical risk factors for PE; xi) novel therapies for the prevention and treatment of PE; xii) long-term cardiovascular consequences of PE and xiii) patient perspectives. Based on these discussions, recommendations for future research were developed in the following general areas: 1) Pathophysiology of PE; 2) Impact of PE on long-term health outcomes; 3) Biomarkers and diagnostic tools; 4) Translational research and novel treatment strategies. The purpose of this report is to summarize the scientific research recommendations arising from deliberations of the invited speakers and meeting attendees. These research recommendations are summarized in Table 1 (which is keyed to the manuscript text) and are presented in no particular order of priority. The goal of the recommendations is to provide guidance regarding future research on PE and its short- and long-term consequences. Table1: Summary of recommendations from the NIH workshop on “Predicting, Preventing and Treating Preeclampsia”

Fetal tissue is ‘gold standard’ for key studies, NIH workshop concludes

Fetal tissue is ‘gold standard’ for key studies, NIH workshop concludes

Working toward precision medicine approaches to treat severe obesity in adolescents: report of an NIH workshop.

Adolescent severe obesity is a prevalent, chronic, and serious disease with few effective and safe treatment options. To address this issue, a National Institutes of Health-sponsored workshop entitled "Developing Precision Medicine Approaches to the Treatment of Severe Obesity in Adolescents," was convened, bringing together a multidisciplinary group of experts to review the current state of the science and identify (1) what is known regarding the epidemiology and biopsychosocial determinants of severe obesity in adolescents, (2) what is known regarding effectiveness of treatments for severe obesity in adolescents and predictors of response, and (3) gaps and opportunities for future research to develop more effective and targeted treatments for adolescents with severe obesity. Major topical areas discussed at the workshop included: appropriate BMI metrics, valid measures of phenotypes and predictors, mechanisms associated with the development of severe obesity, novel treatments informed by biologically and psychosocially plausible mechanisms, biopsychosocial phenotypes predicting treatment response, standardization of outcome measures and results reporting in research, and improving clinical care. Substantial gaps in knowledge were identified regarding the basic behavioral, psychosocial, and biological mechanisms driving the development of severe obesity and the influence of these factors on treatment response. Additional exploratory and observational studies are needed to better understand the heterogeneous etiology of severe obesity and explain the high degree of variability observed with interventions. Tailored treatment strategies that may be developed by achieving a better understanding of individual differences in genetic endowment, clinical, metabolic, psychological, and behavioral phenotypes, and response to environmental exposures need to be tested. It is anticipated that these recommendations for future research, including strategies to enhance methodological rigor, will advance precision medicine approaches to treat severe obesity in adolescents more effectively.

Analysis of intratumor heterogeneity in Neurofibromatosis type 1 plexiform neurofibromas and neurofibromas with atypical features: Correlating histological and genomic findings.

Plexiform neurofibromas (PNFs) are benign peripheral nerve sheath tumors involving large nerves present in 30%-50% Neurofibromatosis type 1 (NF1) patients. Atypical neurofibromas (ANF) are distinct nodular lesions with atypical features on histology that arise from PNFs. The risk and timeline of malignant transformation in ANF is difficult to assess. A recent NIH workshop has stratified ANFs and separated a subgroup with multiple atypical features and higher risk of malignant transformation termed atypical neurofibromatous neoplasms with uncertain biological potential (ANNUBP). We performed an analysis of intratumor heterogeneity on eight PNFs to link histological and genomic findings. Tumors were homogeneous although histological and molecular heterogeneity was identified. All tumors were 2n, almost mutation-free and had a clonal NF1(-/-) origin. Two ANFs from the same patient showed atypical features on histology and deletions of CDKN2A/B. One of the ANFs exhibited different areas in which the degree of histological atypia correlated with the heterozygous or homozygous loss of the CDKN2A/B loci. CDKN2A/B deletions in different areas originated independently. Results may indicate that loss of a single CDKN2A/B copy in NF1(-/-) cells is sufficient to start ANF development and that total inactivation of both copies of CDKN2A/B is necessary to form an ANNUBP.

Indoor Environmental Interventions and their Effect on Asthma Outcomes.

The use of environmental interventions to improve outcomes in asthmatics has long been an elusive goal. While numerous interventions have been studied, the results of clinical trials have been mixed. This review aims to identify combinations of interventions that have been proven to be effective and to propose a model for using them in a clinical setting. An NIH workshop emphasized a need for research to identify effective interventions for reducing indoor exposures and improving asthma outcomes. A number of innovative measures were described, though evidence supporting their use was lacking. A recent systematic review described various interventions for which evidence is available. The greatest challenge for this approach is the same as that for the medical approach to treatment: nonadherence. Given evidence for effective interventions, control of environmental exposures should lead to improved asthma outcomes. Methods to improve adherence need to be identified.

The changing relationship between bronchopulmonary dysplasia and cognition in very preterm infants.

To characterise the relationship between bronchopulmonary dysplasia (BPD) severity and cognition in the post-surfactant era. This was a single-centre retrospective analysis of a cohort of infants born 2009-2012. Inclusion criteria were as follows: admission within 48 hours of birth, gestational age 22-0/7-31-6/7 weeks, birthweight 400-1500 g and Bayley Scales of Infant and Toddler Development-III testing at 18-26 months corrected age. Infants (n = 151) were classified by BPD severity with the NIH Workshop definition. Generalised linear modelling and multivariate logistic regression were performed. Bayley cognitive score was not associated with BPD severity in univariate (p = 0.053) or multivariate (p = 0.503) analysis. About 27% of infants with no/mild BPD, 33% of infants with moderate BPD and 40% of infants with severe BPD had a cognitive score <85. There was no difference in the odds of cognitive score <85 based on BPD severity in univariate (p = 0.485) or multivariate analysis (p = 0.225). All infants with cognitive score <70 had severe BPD, although the association between cognitive score <70 and BPD severity was not significant. We found no independent effect of BPD severity level on cognition. The likelihood of a cognitive score <85 was not associated with BPD severity.

Integrating themes, evidence gaps, and research needs identified by workshop on iron screening and supplementation in iron-replete pregnant women and young children

This report addresses the evidence and the uncertainties, knowledge gaps, and research needs identified by participants at the NIH workshop related to iron screening and routine iron supplementation of largely iron-replete pregnant women and young children (6-24 mo) in developed countries. The workshop presentations and panel discussions focused on current understanding and knowledge gaps related to iron homeostasis, measurement of and evidence for iron status, and emerging concerns about supplementing iron-replete members of these vulnerable populations. Four integrating themes emerged across workshop presentations and discussion and centered on 1) physiologic or developmental adaptations of iron homeostasis to pregnancy and early infancy, respectively, and their implications, 2) improvement of the assessment of iron status across the full continuum from iron deficiency anemia to iron deficiency to iron replete to iron excess, 3) the linkage of iron status with health outcomes beyond hematologic outcomes, and 4) the balance of benefit and harm of iron supplementation of iron-replete pregnant women and young children. Research that addresses these themes in the context of the full continuum of iron status is needed to inform approaches to the balancing of benefits and harms of screening and routine supplementation.

Biological control of appetite: A daunting complexity.

ObjectiveThis review summarizes a portion of the discussions of an NIH Workshop (Bethesda, MD, 2015) entitled, “Self-Regulation of Appetite, It's Complicated,” which focused on the biological aspects of appetite regulation.MethodsHere we summarize the key biological inputs of appetite regulation and their implications for body weight regulation.ResultsThese discussions offer an update of the long-held, rigid perspective of an “adipocentric” biological control, taking a broader view that also includes important inputs from the digestive tract, from lean mass, and from the chemical sensory systems underlying taste and smell. We are only beginning to understand how these biological systems are integrated and how this integrated input influences appetite and food eating behaviors. The relevance of these biological inputs was discussed primarily in the context of obesity and the problem of weight regain, touching on topics related to the biological predisposition for obesity and the impact that obesity treatments (dieting, exercise, bariatric surgery, etc.) might have on appetite and weight loss maintenance. Finally, we consider a common theme that pervaded the workshop discussions, which was individual variability.ConclusionsIt is this individual variability in the predisposition for obesity and in the biological response to weight loss that makes the biological component of appetite regulation so complicated. When this individual biological variability is placed in the context of the diverse environmental and behavioral pressures that also influence food eating behaviors, it is easy to appreciate the daunting complexities that arise with the self-regulation of appetite.

Appetite self-regulation: Environmental and policy influences on eating behaviors.

Appetite regulation is influenced by the environment, and the environment is shaped by food-related policies. This review summarizes the environment and policy research portion of an NIH Workshop (Bethesda, MD, 2015) titled "Self-Regulation of Appetite-It's Complicated." In this paper, we begin by making the case for why policy is an important tool in efforts to improve nutrition, and we introduce an ecological framework that illustrates the multiple layers that influence what people eat. We describe the state of the science on how policies influence behavior in several key areas: the federal food programs, schools, child care, food and beverage pricing, marketing to youth, behavioral economics, and changing defaults. Next, we propose novel approaches for multidisciplinary prevention and intervention strategies to promote breastfeeding, and examine interactions between psychology and the environment. Policy and environmental change are the most distal influences on individual-level appetite regulation, yet these strategies can reach many people at once by changing the environment in which food choices are made. We note the need for more research to understand compensatory behavior, reactance, and how to effectively change social norms. To move forward, we need a more sophisticated understanding of how individual psychological and biological factors interact with the environment and policy influences.