Mutations in the DMD gene cause fatal Duchenne Muscular Dystrophy (DMD). An attractive therapeutic approach is autologous cell transplantation utilizing myogenic progenitors derived from induced pluripotent stem cells (iPSCs). Given that a significant number of DMD mutations occur between exons 45 and 55, we developed a gene knock-in approach to correct any mutations downstream of exon 44. We applied this approach to two DMD patient-specific iPSC lines carrying mutations in exons 45 and 51 and confirmed mini-DYSTROPHIN (mini-DYS) protein expression in corrected myotubes by western blot and immunofluorescence staining. Transplantation of gene-edited DMD iPSC-derived myogenic progenitors into NSG/mdx4Cv mice produced donor-derived myofibers, as shown by the dual expression of human DYSTROPHIN and LAMIN A/C. These findings further provide proof-of-concept for the use of programmable nucleases for the development of autologous iPSC-based therapy for muscular dystrophies.

Pluripotent stem cell (PSC)-based cell therapy is an attractive option for the treatment of multiple human disorders, including muscular dystrophies. While in vitro differentiating PSCs can generate large numbers of human lineage-specific tissue, multiple studies evidenced that these cell populations mostly display embryonic/fetal features. We previously demonstrated that transplantation of PSC-derived myogenic progenitors provides long-term engraftment and functional improvement in several dystrophic mouse models, but it remained unknown whether donor-derived myofibers mature to match adult tissue. Here, we transplanted iPAX7 myogenic progenitors into muscles of non-dystrophic and dystrophic mice and compared the transcriptional landscape of human grafts with respective in vitro-differentiated iPAX7 myotubes as well as human skeletal muscle biospecimens. Pairing bulk RNA sequencing with computational deconvolution of human reads, we were able to pinpoint key myogenic changes that occur during the in vitro-to-in vivo transition, confirm developmental maturity, and consequently evaluate their applicability for cell-based therapies.

Pluripotent stem (PS) cells enable the scalable production of tissue-specific derivatives with therapeutic potential for various clinical applications, including muscular dystrophies. Given the similarity to human counterparts, the non-human primate (NHP) is an ideal preclinical model to evaluate several questions, including delivery, biodistribution, and immune response. While the generation of human-induced PS (iPS)-cell-derived myogenic progenitors is well established, there have been no data for NHP counterparts, probably due to the lack of an efficient system to differentiate NHP iPS cells towards the skeletal muscle lineage. Here, we report the generation of three independent Macaca fascicularis iPS cell lines and their myogenic differentiation using PAX7 conditional expression. The whole-transcriptome analysis confirmed the successful sequential induction of mesoderm, paraxial mesoderm, and myogenic lineages. NHP myogenic progenitors efficiently gave rise to myotubes under appropriate in vitro differentiation conditions and engrafted in vivo into the TA muscles of NSG and FKRP-NSG mice. Lastly, we explored the preclinical potential of these NHP myogenic progenitors in a single wild-type NHP recipient, demonstrating engraftment and characterizing the interaction with the host immune response. These studies establish an NHP model system through which iPS-cell-derived myogenic progenitors can be studied.

"Research Accomplishments in Pulmonary, Critical Care and Sleep: A Retrospective Review." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.

EditorialThe intersection of women’s health, lung health, and diseaseMarrah E. Lachowicz-Scroggins, Louis J. Vuga, Aaron D. Laposky, Marishka Brown, Koyeli Banerjee, Thomas L. Croxton, and James P. KileyMarrah E. Lachowicz-ScrogginsDivision of Lung Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, Louis J. VugaDivision of Lung Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, Aaron D. LaposkyDivision of Lung Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, Marishka BrownDivision of Lung Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, Koyeli BanerjeeDivision of Lung Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, Thomas L. CroxtonDivision of Lung Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, and James P. KileyDivision of Lung Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MarylandPublished Online:07 Sep 2021https://doi.org/10.1152/ajplung.00333.2021This is the final version - click for previous versionMoreSectionsPDF (454 KB)Download PDFDownload PDFPlus ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmail INTRODUCTIONWe celebrate World Lung Day 2021 with a somber tone, realizing that the past year has likely seen more deaths related to lung disease than at any other point in our lifetimes. The COVID-19 pandemic has provided both an unwelcome reminder of the lung’s vulnerability to environmental microbes and toxins and a striking demonstration of how scientific research can improve care and patient outcomes. Respiratory health providers—pulmonary and critical care physicians and respiratory therapists—have shown extraordinary dedication, consummate skill, and even heroism in responding to COVID-19, and it is noteworthy that the medical community associated with this journal has never looked better. But the pandemic has also shown light on how little we understand about individual factors that determine lung susceptibility and resilience—factors such as age, race/ethnicity, and sex/gender. In particular, males have suffered more from COVID-19 than females, both by cases and by deaths (1, 2). This is especially interesting because it is opposite to what is typical for chronic lung diseases, namely, a slight to threefold predominance of female cases. The pandemic reminds us not only of the need to address health inequities but also of the complexity of that issue, which often interweaves women and men differently among the threads of race, poverty, geography, environment, education, and health-care access (3, 4). In this editorial, we look beyond the pandemic and highlight women’s lung health—a longstanding issue that would benefit from greater research interest and intensity.BIOLOGICAL AND ENVIRONMENTAL BASES OF SEX/GENDER DIFFERENCES IN LUNG HEALTH AND DISEASEWomen’s lung health has roots in the prenatal period when sex hormones and exposures in the womb drive differences in early lung development, anatomy, and physiology (3). Sex differences in lung development and maturation can be observed as early as 16 wk of gestation, where androgens increase airway branching in males resulting in larger lungs with more bronchioles at birth (4). In adulthood, these prenatal androgen exposures result in larger airway diameters, more alveoli, and increased lung volume in men when compared with women (5). Sex, hormones, and gender continue to impact lung health across the lifespan with differences in risk, susceptibility, and resilience to lung diseases (6, 7). Effects of sex steroids on chronic lung diseases often involve their roles in immune cell function and lung inflammation (8), but this biological difference is insufficient to explain the diverse and profound differences in morbidity and mortality that women experience throughout their lifetimes (9, 10). Gender differences are also driven by a host of external factors (11, 12). Research on women’s health must consider both the biological perspective, which operates at the genetic, molecular, cellular, and physiological levels and the social/environmental perspective, which operates at the individual, community, and societal levels.IMPACT OF CHRONIC LUNG DISEASES ON WOMEN’S HEALTHSex and gender have key roles in disparities for chronic lung diseases. Chronic pulmonary diseases have high morbidity and are the third leading cause of death for women in the United States (13). Both epidemiology and clinical presentation for chronic lung disease can differ between women and men. Asthma prevalence is more common in boys during childhood; however, incidence rates increase for girls around puberty when rates decrease in males (14). In adulthood, asthma is more prevalent in women regardless of race, and exacerbation rates, hospitalizations, and mortality are higher among women (15). Asthma severity can also be modulated by body weight and sex hormones (16). In the United States, rates for chronic obstructive pulmonary disease (COPD) in women have been rising since 2008 and now exceed those of men. COPD is a leading cause of death among women, particularly those with comorbidities (17). A notably different example is how sex can alter disease course in cystic fibrosis (CF) with what is known as the “CF Gender Gap.” In CF, estrogen has profound impact on the virulence of Pseudomonas aeruginosa and the formation of biofilms which enable bacterial persistence (18). Similar mechanisms may contribute in other chronic lung diseases associated with bronchiectasis, where there are clear gender differences in onset, association to underlying disease, morbidity, and mortality (19). Other mechanisms are likely at play in autoimmune diseases affecting the lung, which include sarcoidosis, systemic sclerosis (SSc), rheumatoid arthritis (RA), Sjogren’s syndrome, and systemic lupus erythematosus—all of which are more common in women than men (20). The pulmonary impact of autoimmune diseases may be aggravated by co-occurring pulmonary arterial hypertension (PAH), which is often progressive leading to right heart failure and death. Women are twice as likely than men to develop PAH (21), including in the context of autoimmune disease. PAH in patients with SSc who develop interstitial lung disease is associated with increased morbidity, resistance to PAH therapy, and overall poorer health outcomes (22, 23). As systemic sclerosis occurs more commonly in women, they represent an at-risk group for PAH (24, 25). An even more prevalent autoimmune condition with increased rates of lung disease is rheumatoid arthritis. The rate of RA in women is nearly threefold greater than in men, with earlier disease onset and highest incidence around menopause. Extra-articular manifestations include several forms of interstitial lung diseases with clear sex differences in clinical presentation (26, 27). Another autoimmune condition that is more common among women is sarcoidosis. Although the cause of sarcoidosis remains unknown, evidence suggests that underlying genetic and other risk factors for sarcoidosis include sex, race, socioeconomic status, and gene-environment interactions (GxE) (28).SLEEP DISPARITIES IN WOMEN’S HEALTHObstructive sleep apnea (OSA) is a serious medical condition characterized by repetitive episodes of partial or complete upper airway collapse during sleep, resulting in restricted airflow, oxygen desaturation, and sleep fragmentation. Conservatively, 4%–7% of women exhibit OSA, with higher prevalence in women who are overweight/obese, postmenopausal, and pregnant (29, 30). Sleep apnea is associated with increased risk for many conditions impacting women, including cardiovascular disease, diabetes, depression, cancer, and dementia (31). Although OSA is treatable, the majority of women with OSA fail to receive an appropriate diagnosis (29). The classic stereotype for OSA is an obese, middle-aged male with chronic snoring and excessive daytime sleepiness; however, important sex/gender differences exist in clinical presentation. Women with OSA more frequently report fatigue, depression, anxiety, insomnia, and difficulty sleeping—symptoms that are not primarily queried in most apnea risk assessment tools. Research is needed to improve methods for apnea risk detection, reducing bias due to sex differences in symptom presentation. The diagnosis of OSA is based on the apnea-hypopnea index (AHI), which measures the number of apneas and hypopneas that occur per hour of sleep. Women tend to have lower AHI compared with men, shorter duration of apneas, and less severe oxygen desaturation, but in certain cases, the health risks they incur associated with apnea are the same or even greater than in men (e.g., elevated high-sensitivity cardiac troponin levels, increased left ventricular mass, incident heart failure, impaired endothelial function, and brain white matter loss) (10). Furthermore, recent studies have shown that women are susceptible to subtle airflow limitation (AFL), which does not meet AHI criteria but nonetheless triggers arousal from sleep, sympathetic activation, and potentially other pathophysiological effects (32). These findings suggest that assessment and diagnostic criteria may need to be redefined, considering sex/gender-specific sleep-disordered breathing symptoms and clinical phenotypes.SEX/GENDER DIFFERENCES IN SARS-CoV-2 INFECTIONSex/gender differences are apparent both during acute infection with SARS-CoV-2 and for the postacute sequelae of COVID-19 (PASC, “long-COVID”). Research in this area is perhaps a model for that on other diseases, since the norm has been to report results in a sex-disaggregated manner and to routinely consider sex as a biological variable (SABV) in COVID-related studies (33, 34). This rigor has quickly yielded compelling data on sex and racial disparities in COVID-19 with the level of detail that is needed for nuanced interpretations. For example, a recent publication confirmed that, although men have higher mortality rates than women overall, this sex disparity does not hold across racial groups (35, 36). In fact, COVID-19 mortality rates for Black women are higher than rates for both men and women of either White or Asian/Pacific Islander ancestry. In addition, women appear to be much more prone to developing PASC, as evidenced by greater morbidity and health-care utilization after COVID infection (37).CONCLUSIONSThis brief overview of women’s lung health illuminates many opportunities for research. It remains critically important for all clinical researchers to include adequate numbers of women in their study populations and to report results in a sex-disaggregated manner. There is also a need for specifically designed studies to investigate the etiology origins of sex/gender differences and to develop and test approaches for reducing disparities. A crude analysis of the grant portfolio of the Division of Lung Disease, using the NIH Research, Condition, and Disease Categorization (RCDC) system, suggests that among all grants on lung diseases funded by National Heart, Lung, and Blood Institute (NHLBI) in the past 5 years (Fig. 1), only 3% are specifically directed to issues of women’s health. NIH is taking positive action to address this situation. In May 2014, NIH stated clearly that rigor and transparency in research requires researchers to account for sex as a biological variable (SABV), and NIH identified this as a requirement in most NIH-funded research. This was expanded in 2018 to include consideration of age across the lifespan. These policies have implications for preclinical research (38), and they encourage the research community to go well beyond the simple inclusion of both sexes in their studies. For example, we need clinical study/trial designs that test strategies for personalized medicine that are inspired by the distinctive risks and disease mechanisms of women (13, 38). Although we affirm efforts by the research community to improve transparency and rigor in the reporting of clinical research studies (39), the time has come to move beyond the use of metrics developed and validated in male-dominated studies (e.g., sleep apnea, AHI) and that test interventions that target mechanisms that are particularly relevant to diseases as experienced by women. Furthermore, future research on women’s health should not only investigate biological differences associated with sex/gender but also explore how women are affected by disease in the broad context of external factors such as social determinants of health. To address these disparities in lung health across the lifespan research in health education, early intervention and primary prevention are areas much in need of stimulation (40, 41). This type of interdisciplinary work may be aided by expanding the capacity of the research community, especially with regard to recruitment and advancement of women scientists. NIH provides tangible support for such efforts through the Building Interdisciplinary Research Careers in Women’s Health (BIRCWH) K12 program (42). NHLBI wholly supports the 2019–2023 Trans-NIH Strategic Plan for Women’s Health Research (43) and is further advancing research on women’s health through the Institute’s Strategic Vision and through the creation of a Women’s Health Working Group in 2015 (44). We encourage the research community to partner with us to better understand the role of sex/gender in lung health through interdisciplinary research and to work toward the elimination of disparities in lung health. World Lung Day 2021 is an opportune time to reflect not only on the seriousness of lung disease but also on the tremendous opportunities that exist today for impactful research that can improve lung health for every member of our societies.Figure 1.National Heart, Lung, and Blood Institute Fiscal Years 2016–2020 Division of Lung Diseases and Women’s Health Portfolio.Download figureDownload PowerPointDISCLAIMERSThe views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the US Department of Health and Human Services.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the authors.AUTHOR CONTRIBUTIONSM.E.L.-S., L.J.V., A.L., M.B., K.B., T.L.C., and J.P.K. drafted manuscript; edited and revised manuscript; and approved final version of manuscript.REFERENCES1. Takahashi T, Iwasaki A. Sex differences in immune responses. Science 371: 347–348, 2021. doi:10.1126/science.abe7199. Crossref | PubMed | ISI | Google Scholar2. Bunders MJ, Altfeld M. Implications of sex differences in immunity for SARS-CoV-2 pathogenesis and design of therapeutic interventions. Immunity 53: 487–495, 2020. doi:10.1016/j.immuni.2020.08.003. Crossref | PubMed | ISI | Google Scholar3. Kocurek EG, Hemnes AR. Women’s health and lung development and disease. Obstet Gynecol Clin North Am 43: 307–323, 2016. doi:10.1016/j.ogc.2016.01.003. Crossref | PubMed | ISI | Google Scholar4. Seaborn T, Simard M, Provost PR, Piedboeuf B, Tremblay Y. Sex hormone metabolism in lung development and maturation. Trends Endocrinol Metab 21: 729–738, 2010. doi:10.1016/j.tem.2010.09.001. Crossref | PubMed | ISI | Google Scholar5. Hanna GM, Daniels CL, Berend N. The relationship between airway size and lung size. Br J Dis Chest 79: 183–188, 1985. doi:10.1016/0007-0971(85)90029-4. Crossref | PubMed | Google Scholar6. Liptzin DR, Landau LI, Taussig LM. Sex and the lung: observations, hypotheses, and future directions. Pediatr Pulmonol 50: 1159–1169, 2015. doi:10.1002/ppul.23178. Crossref | PubMed | ISI | Google Scholar7. Sathish V, Martin YN, Prakash YS. Sex steroid signaling: implications for lung diseases. Pharmacol Ther 150: 94–108, 2015. doi:10.1016/j.pharmthera.2015.01.007. Crossref | PubMed | ISI | Google Scholar8. Reyes-García J, Montaño LM, Carbajal-García A, Wang YX. Sex hormones and lung inflammation. Adv Exp Med Biol 1304: 259–321, 2021. doi:10.1007/978-3-030-68748-9_15.Crossref | PubMed | ISI | Google Scholar9. Carey MA, Card JW, Voltz JW, Arbes SJ Jr, Germolec DR, Korach KS, Zeldin DC. It’s all about sex: gender, lung development and lung disease. Trends Endocrinol Metab 18: 308–313, 2007. doi:10.1016/j.tem.2007.08.003. Crossref | PubMed | ISI | Google Scholar10. Han MK, Arteaga-Solis E, Blenis J, Bourjeily G, Clegg DJ, DeMeo D, Duffy J, Gaston B, Heller NM, Hemnes A, Henske EP, Jain R, Lahm T, Lancaster LH, Lee J, Legato MJ, McKee S, Mehra R, Morris A, Prakash YS, Stampfli MR, Gopal-Srivastava R, Laposky AD, Punturieri A, Reineck L, Tigno X, Clayton J. 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. Am J Respir Crit Care Med 198: 850–858, 2018. doi:10.1164/rccm.201801-0168WS. Crossref | PubMed | ISI | Google Scholar11. Silveyra P, Fuentes N, Rodriguez Bauza DE. Sex and gender differences in lung disease. Adv Exp Med Biol 1304: 227–258, 2021.doi:10.1007/978-3-030-68748-9_14. Crossref | PubMed | Google Scholar12. Schweinhart A, Clayton JA. Reversing the trends toward shorter lives and poorer health for U.S. women: a call for innovative interdisciplinary research. Int J Environ Res Public Health 15: 1796, 2018.doi:10.3390/ijerph15091796.Crossref | PubMed | ISI | Google Scholar13. Mauvais-Jarvis F, Bairey Merz N, Barnes PJ, Brinton RD, Carrero J-J, DeMeo DL, De Vries GJ, Epperson CN, Govindan R, Klein SL, Lonardo A, Maki PM, McCullough LD, Regitz-Zagrosek V, Regensteiner JG, Rubin JB, Sandberg K, Suzuki A. Sex and gender: modifiers of health, disease, and medicine. Lancet 396: 565–582, 2020 [Erratum in Lancet 396: 668, 2020]. doi:10.1016/S0140-6736(20)31561-0. Crossref | PubMed | ISI | Google Scholar14. Johnson CC, Havstad SL, Ownby DR, Joseph CLM, Sitarik AR, Biagini Myers J, Gebretsadik T, Hartert TV, Khurana Hershey GK, Jackson DJ, Lemanske RF Jr, Martin LJ, Zoratti EM, Visness CM, Ryan PH, Gold DR, Martinez FD, Miller RL, Seroogy CM, Wright AL, Gern JE; Children’s Respiratory and Environmental Workgroup in the ECHO Consortium. Pediatric asthma incidence rates in the United States from 1980 to 2017. J Allergy Clin Immunol. In press. doi:10.1016/j.jaci.2021.04.027.Crossref | PubMed | Google Scholar15. Pignataro FS, Bonini M, Forgione A, Melandri S, Usmani OS. Asthma and gender: the female lung. Pharmacol Res 119: 384–390, 2017. doi:10.1016/j.phrs.2017.02.017. Crossref | PubMed | ISI | Google Scholar16. Khalid F, Holguin F. A review of obesity and asthma across the life span. J Asthma 55: 1286–1300, 2018. doi:10.1080/02770903.2018.1424187. Crossref | PubMed | ISI | Google Scholar17. Gut-Gobert C, Cavaillès A, Dixmier A, Guillot S, Jouneau S, Leroyer C, Marchand-Adam S, Marquette D, Meurice JC, Desvigne N, Morel H, Person-Tacnet C, Raherison C. Women and COPD: do we need more evidence? Eur Respir Rev 28: 180055, 2019.doi:10.1183/16000617.0055-2018.Crossref | PubMed | ISI | Google Scholar18. Tyrrell J, Harvey BJ. Sexual dimorphism in the microbiology of the CF ‘Gender Gap’: estrogen modulation of Pseudomonas aeruginosa virulence. Steroids 156: 108575, 2020. doi:10.1016/j.steroids.2019.108575. Crossref | PubMed | ISI | Google Scholar19. Vidaillac C, Yong VFL, Jaggi TK, Soh M-M, Chotirmall SH. Gender differences in bronchiectasis: a real issue? Breathe (Sheff) 14: 108–121, 2018. doi:10.1183/20734735.000218. Crossref | PubMed | ISI | Google Scholar20. Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 84: 223–243, 1997. doi:10.1006/clin.1997.4412. Crossref | PubMed | Google Scholar21. Memon HA, Park MH. Pulmonary arterial hypertension in women. Methodist Debakey Cardiovasc J 13: 224–237, 2017. doi:10.14797/mdcj-13-4-224. Crossref | PubMed | Google Scholar22. Chung L, Liu J, Parsons L, Hassoun PM, McGoon M, Badesch DB, Miller DP, Nicolls MR, Zamanian RT. Characterization of connective tissue disease-associated pulmonary arterial hypertension from REVEAL: identifying systemic sclerosis as a unique phenotype. Chest 138: 1383–1394, 2010. doi:10.1378/chest.10-0260. Crossref | PubMed | ISI | Google Scholar23. Ramjug S, Hussain N, Hurdman J, Billings C, Charalampopoulos A, Elliot CA, Kiely DG, Sabroe I, Rajaram S, Swift AJ, Condliffe R. Idiopathic and systemic sclerosis-associated pulmonary arterial hypertension: a comparison of demographic, hemodynamic, and MRI characteristics and outcomes. Chest 152: 92–102, 2017. doi:10.1016/j.chest.2017.02.010. Crossref | PubMed | ISI | Google Scholar24. Steen VD, Oddis CV, Conte CG, Janoski J, Casterline GZ, Medsger TA Jr. Incidence of systemic sclerosis in Allegheny County, Pennsylvania. A twenty-year study of hospital-diagnosed cases, 1963–1982. Arthritis Rheum 40: 441–445, 1997. doi:10.1002/art.1780400309. Crossref | PubMed | Google Scholar25. Bergamasco A, Hartmann N, Wallace L, Verpillat P. Epidemiology of systemic sclerosis and systemic sclerosis-associated interstitial lung disease. Clin Epidemiol 11: 257–273, 2019. doi:10.2147/CLEP.S191418. Crossref | PubMed | ISI | Google Scholar26. Linos A, Worthington JW, O’Fallon WM, Kurland LT. The epidemiology of rheumatoid arthritis in Rochester, Minnesota: a study of incidence, prevalence, and mortality. Am J Epidemiol 111: 87–98, 1980. doi:10.1093/oxfordjournals.aje.a112878. Crossref | PubMed | ISI | Google Scholar27. Doyle TJ, Patel AS, Hatabu H, Nishino M, Wu G, Osorio JC, Golzarri MF, Traslosheros A, Chu SG, Frits ML, Iannaccone CK, Koontz D, Fuhrman C, Weinblatt ME, El-Chemaly SY, Washko GR, Hunninghake GM, Choi AM, Dellaripa PF, Oddis CV, Shadick NA, Ascherman DP, Rosas IO. Detection of rheumatoid arthritis-interstitial lung disease is enhanced by serum biomarkers. Am J Respir Crit Care Med 191: 1403–1412, 2015. doi:10.1164/rccm.201411-1950OC. Crossref | PubMed | ISI | Google Scholar28. Rivera NV, Patasova K, Kullberg S, Diaz-Gallo LM, Iseda T, Bengtsson C, Alfredsson L, Eklund A, Kockum I, Grunewald J, Padyukov L. A gene-environment interaction between smoking and gene polymorphisms provides a high risk of two subgroups of sarcoidosis. Sci Rep 9: 18633, 2019. doi:10.1038/s41598-019-54612-1. Crossref | PubMed | ISI | Google Scholar29. Ayub S, Won CHJ. Obstructive sleep apnea in women. J Sleep Med 16: 75–80, 2019. doi:10.13078/jsm.190047.Crossref | Google Scholar30. Laposky AD, Pemberton VL. Sleep-disordered breathing and pregnancy-related cardiovascular disease. J Womens Health (Larchmt) 30: 194–198, 2021. doi:10.1089/jwh.2020.8869. Crossref | PubMed | ISI | Google Scholar31. Wimms A, Woehrle H, Ketheeswaran S, Ramanan D, Armitstead J. Obstructive sleep apnea in women: specific issues and interventions. Biomed Res Int 2016: 1764837, 2016. doi:10.1155/2016/1764837. Crossref | PubMed | ISI | Google Scholar32. Link BN, Eid C, Bublitz MH, Pengo MF, Salameh M, Ludwig KS, Millman RP, Dworkin L, Bourjeily G. Pulse transit time in pregnancy: a new way to diagnose and classify sleep disordered breathing? Sleep 42: zsz022, 2019. doi:10.1093/sleep/zsz022.Crossref | PubMed | ISI | Google Scholar33. Ryan NE, El Ayadi AM. A call for a gender-responsive, intersectional approach to address COVID-19. Glob Public Health 15: 1404–1412, 2020. doi:10.1080/17441692.2020.1791214. Crossref | PubMed | ISI | Google Scholar34. Wenham C, Smith J, Morgan R; Gender and COVID-19 Working Group. COVID-19: the gendered impacts of the outbreak. The Lancet 395: 846–848, 2020. doi:10.1016/S0140-6736(20)30526-2. Crossref | PubMed | ISI | Google Scholar35. Rushovich T, Boulicault M, Chen JT, Danielsen AC, Tarrant A, Richardson SS, Shattuck-Heidorn H. Sex disparities in COVID-19 mortality vary across US racial groups. J Gen Intern Med 36: 1696–1701, 2021. doi:10.1007/s11606-021-06699-4. Crossref | PubMed | ISI | Google Scholar36. Kopel J, Perisetti A, Roghani A, Aziz M, Gajendran M, Goyal H. Racial and gender-based differences in COVID-19. Front Public Health 8: 418, 2020. doi:10.3389/fpubh.2020.00418. Crossref | PubMed | ISI | Google Scholar37. Davido B, Seang S, Tubiana R, de Truchis P. Post–COVID-19 chronic symptoms: a postinfectious entity? Clin Microbiol Infect 26: 1448–1449, 2020. doi:10.1016/j.cmi.2020.07.028. Crossref | PubMed | ISI | Google Scholar38. Clayton JA. Studying both sexes: a guiding principle for biomedicine. FASEB J 30: 519–524, 2016. doi:10.1096/fj.15-279554. Crossref | PubMed | ISI | Google Scholar39. Clayton JA, Tannenbaum C. Reporting sex, gender, or both in clinical research? JAMA 316: 1863–1864, 2016. doi:10.1001/jama.2016.16405. Crossref | PubMed | ISI | Google Scholar40. von Mutius E, Smits HH. Primary prevention of asthma: from risk and protective factors to targeted strategies for prevention. Lancet 396: 854–866, 2020. doi:10.1016/S0140-6736(20)31861-4. Crossref | PubMed | ISI | Google Scholar41. Drummond MB, Buist AS, Crapo JD, Wise RA, Rennard SI. Chronic obstructive pulmonary disease: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases. Ann Am Thorac Soc 11, Suppl 3: S154–S160, 2014. doi:10.1513/AnnalsATS.201312-432LD.Crossref | PubMed | Google Scholar42. Libby AM, McGinnes HG, Regensteiner JG. Educating the scientific workforce on sex and gender considerations in research: a national scan of the literature and building interdisciplinary research careers in women’s health programs. J Womens Health (Larchmt) 29: 876–885, 2020. doi:10.1089/jwh.2019.8067. Crossref | PubMed | ISI | Google Scholar43. National Institutes of Health Office of Research on Women’s Health. Trans-NIH Strategic Plan for Women's Health Research (Online). https://orwh.od.nih.gov/sites/orwh/files/docs/ORWH_Strategic_Plan_2019_508C_0.pdf.Google Scholar44. National Institutes of Health National Heart, Lung, and Blood Institute. The NHLBI Strategic Vision (Online). https://www.nhlbi.nih.gov/sites/default/files/2017-11/NHLBI-Strategic-Vision-2016_FF.pdf.Google ScholarAUTHOR NOTESCorrespondence: J. P. Kiley ([email protected]nih.gov). Previous Back to Top Next FiguresReferencesRelatedInformationRelated articlesNotable observances in September 2021: sepsis, the lung and heart, pulmonary fibrosis, and peer review in focus 07 Sep 2021American Journal of Physiology-Lung Cellular and Molecular PhysiologyCited ByNotable observances in September 2021: sepsis, the lung and heart, pulmonary fibrosis, and peer review in focusRory E. Morty7 September 2021 | American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol. 321, No. 3 More from this issue > Volume 321Issue 3September 2021Pages L624-L627 Crossmark Copyright & PermissionsPublished by the American Physiological Society.https://doi.org/10.1152/ajplung.00333.2021PubMed34431414History Received 10 August 2021 Accepted 10 August 2021 Published online 7 September 2021 Published in print 1 September 2021 Keywordsgenderlung diseaseNHLBIsexwomen’s health Metrics Downloaded 711 times

Background: The National Institutes of Health (NIH) Loan Repayment Programs (LRPs) were established by Congress in 2000 to help attract and retain highly qualified health professionals in biomedical careers by relieving financial pressure incurred from educational loans obtained during medical school and other advanced-degree clinical training programs. In 2019, the NIH LRP Program increased the maximum repayment from $35,000 per year to $50,000 per year for an individual's educational debt in return for two years of research performed in an NIH mission-relevant area (https://www.lrp. nih.gov/eligibility-programs). In addition, in 2020, the National Heart, Lung, and Blood Institute (NHLBI) increased its participation in the LRP by adding the Health Disparities Research Program to Clinical Research and Pediatric Research Programs. Objective: Before these substantive changes took effect, we sought to determine the impact of the NHLBI's participation in the LRP program on retention of scientists in the biomedical research workforce over the past 20 years. Methods: NHLBI LRP applicant cohorts from 2003 and 2008 were carefully examined with a 10-year follow-up period to measure the impact of applying for and obtaining NIH LRP funding on subsequent K- and R-level application and award rates, publication number, and average relative citation ratio as metrics to assess recruitment and retention of scientists in the biomedical research workforce. Results: Obtaining the LRP award was strongly associated with increased submission of and success in obtaining K- and RPG-grant funding and publications for both the 2003 and 2008 NHLBI LRP cohorts. An analysis of subgroups in the 2008 LRP cohort without prior F, K, or RPG funding revealed a consistently strong association between obtaining an LRP award and subsequent K- or RPG-award submission and success as well as potential synergy between obtaining an LRP award and participation on a T grant toward subsequent K- or RPG-award success rates. Conclusion: The LRP award appears to enhance retention in the biomedical research workforce when measured using metrics of grant application and award rates as well as research publications over a 10-year period.

Mutations in the fukutin-related protein (FKRP) gene result in a broad spectrum of muscular dystrophy (MD) phenotypes, including the severe Walker-Warburg syndrome (WWS). Here, we develop a gene-editing approach that replaces the entire mutant open reading frame with the wild-type sequence to universally correct all FKRP mutations. We apply this approach to correct FKRP mutations in induced pluripotent stem (iPS) cells derived from patients displaying broad clinical severity. Our findings show rescue of functional alpha-dystroglycan (alpha-DG) glycosylation in gene-edited WWS iPS cell-derived myotubes. Transplantation of gene-corrected myogenic progenitors in the FKRPP448L-NSG mouse model gives rise to myofiber and satellite cell engraftment and, importantly, restoration of alpha-DG functional glycosylation in vivo. These findings suggest the potential feasibility of using CRISPR-Cas9 technology in combination with patient-specific iPS cells for the future development of autologous cell transplantation for FKRP-associated MDs.

Inducible expression of PAX7 in differentiating pluripotent stem cells (PSCs) allows massively scalable generation of human myogenic progenitors, which upon transplantation into dystrophic muscles give rise to donor-derived myofibers and satellite cells. Therefore, PSCderived PAX7+ myogenic progenitors represent an attractive therapeutic approach to promote muscle regeneration. Work to date has used lentiviral vectors (LVs) that randomly integrate inducible PAX7 transgenes. Here, we investigated whether equivalent induction of the myogenic program could be achieved by targeting the PAX7 transgene into genomic safe harbor (GSH) sites. Across multiple PSC lines, we find that this approach consistently generates expandable myogenic progenitors in vitro, although scalability of expansion is moderately reduced compared with the LV approach. Importantly, transplantation of GSH-targeted myogenic progenitors produces robust engraftment, comparable with LV counterparts. These findings provide proof of concept for the use of GSH targeting as a potential alternative approach to generate therapeutic PSC-derived myogenic progenitors for clinical applications.

Background We examined feasibility of a unique approach towards gaining insight into heritable risk for early atherosclerosis: surveying gene expression by endothelial cells from living subjects. Methods and Results Subjects aged <50 years (mean age, 37; range, 22–49) without obstructive coronary artery disease underwent coronary reactivity testing that identified them as having normal or abnormal coronary endothelial function. Cultures of Blood Outgrowth Endothelial Cells (BOEC) from 6 normal and 13 abnormal subjects passed rigorous quality control and were used for microarray assessment of gene expression. Of 9 genes differentially expressed at false discovery rate <0.1%, we here focus upon abnormal subjects having elevated expression of HMGB1 (high mobility group box 1) which we unexpectedly found to be linked to low LAMC1 (laminin gamma 1) expression. This linkage was corroborated by 3 of our past studies and confirmed bio‐functionally. Compared with normal BOEC, abnormal BOEC released 13±3‐fold more HMGB1 in response to lipopolysaccharide; and they deposited one tenth as much LAMC1 into collagen subendothelial matrix during culture. Clinical follow‐up data are provided for 4 normal subjects (followed 13.4±0.1 year) and for 12 abnormal subjects (followed 9.1±4.5 years). Conclusions The known pathogenic effects of high‐HMGB1 and low‐LAMC1 predict that the combination would biologically converge upon the focal adhesion complex, to the detriment of endothelial shear responsiveness. This gene expression pattern may comprise a heritable risk state that promotes early coronary atherosclerosis. If so, the testing could be applied even in childhood, enabling early intervention. This approach offers a way to bridge the information gap between genetics and clinical phenotype.

As we recognize World Lung Day on September 25, 2020, our goal as a research community remains to pursue cutting-edge research while maintaining close attention to the immediate needs of patients (33). Even though a particular lung disease may present with a distinctive constellation of signs and symptoms, all lung diseases arise from the same components— the cells, structures, and tissues that make up the respiratory system. Current knowledge of these components, how they work together, how they malfunction, and how they repair themselves lays an important foundation for advances in understanding disease and developing new therapies. Fundamental knowledge of the lung and its components, ranging from physiology over the life span to cellular and molecular function, provides a “toolbox” that can be used to study all diseases of the pulmonary system, even newly emerging diseases such as COVID-19. This editorial highlights the current state of the toolbox for lung research, which is rapidly expanding with new technologies for personal monitoring, single-cell analyses, and data science. This toolbox will allow pulmonary researchers unprecedented capabilities for understanding the heterogeneity of disease, both at a population level and at the cellular and molecular levels, promoting discovery of biomarkers that characterize clinical heterogeneity, aid in prognosis, and guide optimal treatment (35). This toolbox will also promote discovery of cellular or molecular targets for precision medicine interventions. Observational studies have historically taught us about disease risk factors and natural history and have yielded data that can lead to hypotheses regarding mechanisms of pathogenesis. Observational cohort studies also provide a powerful tool to identify correlations, if not causal factors, that may have significant real-world relevance to health and disease. When harmonized for data collection, pooling cohort data can permit researchers to answer questions requiring increased statistical power, such as how lung function decline correlates with smoking cessation and low-intensity smoking (24). Modern observational studies are increasingly able to incorporate a rich collection of data, including clinical, environmental, behavioral, imaging, genetic, and molecular data types, allowing an unprecedented ability to investigate genetic factors that predispose to pulmonary disease (16), identify subclinical phenotypes that predict lung function decline or mortality (2, 14, 34), and use deep phenotyping to identify patient subtypes that might later be used for prognosis or personalized therapies (22, 36). Imaging and molecular data can be used to develop biomarkers or physiological and molecular hypotheses regarding pathogenesis and disease progression. The literature of lung disease research is replete with examples of insights gained through observational studies. Ideally, hypotheses generated from observational studies will be further supported through experimental approaches, although this is not always possible. To realize personalized care for lung disease, patients need to be considered not only as distinct from one another but also as characterized by a unique and dynamic spectrum of pathobiologic processes that converge to ultimately define individual responses to treatments and disease evolution. This concept is illustrated in the focus of asthma mechanistic and clinical research over the past several decades. Key findings illustrate that, although asthma patients may present with similar clinical symptoms, there is significant heterogeneity in disease etiology, pathobiology, disease manifestations, and therapeutic responsiveness. Deep phenotyping approaches have yielded multiscale information that revealed the heterogeneous nature of asthma and exacerbations and distinct disease subtypes. Intrinsic heterogeneity in the pathobiologic processes that underlie asthma, variation in response to therapeutics, and therapeutics that manage or improve the control of symptoms without modifying the underlying disease state or natural history of disease continue to result in significant challenges to optimized clinical care, particularly in those patients with severe disease. Early precision clinical trials, using pathobiologic characteristics, were negative, underscoring the need to integrate pathobiology and clinical symptoms to identify and target specific subpopulations (26). The National Heart, Lung, and Blood Institute’s (NHLBI) Severe Asthma Research Program has significantly contributed to the concept that severe asthma disease heterogeneity and subpopulations result from interactions among multiple, diverse pathobiologic mechanisms over time (8, 10, 25). This evidence base has provided the opportunity to develop more precise, biologically based approaches to optimize asthma clinical management via the NHLBI Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network. The study is using predictive biomarkers and defined patient subgroups in a multistage, adaptive design with novel interventions to optimize management and, potentially, provide the ability to modify disease progression and severity. Another heterogeneous lung disease similar to severe asthma that carries a high mortality rate is acute respiratory distress syndrome (ARDS) (19, 20). The absence of beneficial treatments beyond lung-protective ventilation and regulated fluid management underscores the need to understand disease heterogeneity in order to develop effective therapies. Disease heterogeneity in ARDS stems from a variety of precipitants, including bacterial or viral infections, trauma, or aspiration, as well as heterogeneity of host responses to differing various Correspondence: J. P. Kiley (kileyj@NIH.gov). Am J Physiol Lung Cell Mol Physiol 319: L541–L544, 2020; First published August 12, 2020; doi:10.1152/ajplung.00372.2020.

Mounting scientific evidence links sleep deficiency and sleep disorders to pathobiology in almost every human tissue.Chronic disease and lifestyle factors (e.g.work schedules) are associated with sleep deficiency, disruptions in circadian rhythm, and residual fatigue in an estimated 15%-30% of the general adult population.Economic analyses indicate that the US sustains the highest economic losses world-wide ($411 billion annually, or about 2.3% of gross domestic product) from the repercussions of sleep deficiency including disease burden, lost productivity and accidents, and an array of social determinants underlying health and health disparities [1].In growing recognition of the toll that sleep deficiency and sleep disorders exact on productivity, morbidity, and mortality, Congress established the National Center on Sleep Disorders Research (NCSDR) within the National Institutes of Health (NIH), and National Heart, Lung, and Blood Institute (NHLBI) in 1993 [2].As we approach the quarter-century mark since its creation, it is timely to reflect on the progress of a collaborative, communityengaged approach to public education, discovery, and translational science that portends unparalleled opportunities for sleep and circadian research in the future.

Chronic obstructive pulmonary disease (COPD) is a complex lung disease characterized by airways inflammation and lung tissue remodeling, leading to loss of small airways and emphysema.1 It is the fourth leading cause of death in the United States, responsible for more than 150,000 deaths yearly.2 More than 15 million people have been diagnosed with COPD and, compared to 4.7% in large metropolitan areas, a staggering 8.2% of those living in rural areas have the disease.2 That translates to about 3.5 million people, and it does not include the estimated additional 1 million undiagnosed.2, 3 Notably, even among never-smokers, rural residence and poverty are risk factors for COPD.4 The disease also takes a heavy financial toll: national medical costs associated with COPD are projected to increase from $32.1 billion in 2010 to $49 billion in 2020.5 To tackle COPD, Congress requested that federal and nonfederal partners develop a plan and identify the specific efforts patients, advocates, health care professionals, educators, payors, researchers, the biomedical industry, and federal agencies must take to change the course of COPD. The COPD National Action Plan (CNAP) was released during the 2017 American Thoracic Society International Conference.6 To address COPD in rural populations through the lens of the CNAP, the Health Resources and Services Administration (HRSA) and the National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of rural health representatives and COPD stakeholders in Bethesda, Maryland, on March 19, 2018, to discuss ways to implement each of the 5 goals of the CNAP in rural settings. Below is a summary of the discussions held at the meeting. Educating patients and their caregivers (usually family members) about COPD is the cornerstone of Goal 1. While patient education generally happens in health care facilities, COPD awareness, diagnosis, and care for rural populations also need to reach locations unique to rural settings. Partnering with national rural-focused entities such as the American Agri-Women (AAW) Association, the National Future Farmers of America Organization, Sigma Alpha (a professional agricultural business sorority), and other members of the Consortium of Collegiate Agricultural Organizations can offer additional opportunities to educate about COPD and its prevention. Recognizing rural heterogeneity, culturally, linguistically, and content-appropriate messages need to be crafted for each targeted region. To be sustainable, these programs must develop—with adequate regional, state, and national assistance—local champions. Support could come from groups such as the COPD Foundation, the American Lung Association (ALA), AAW, the National Rural Health Association (NRHA), HRSA's Federal Office of Rural Health Policy, the Veteran Administrations' Office of Rural Health, the Centers for Medicare and Medicaid Services, the states' Primary Care Associations (PCAs), the National Association of Rural Health Clinics, and the National Association of Community Health Centers. Goal 2 of the CNAP stresses the importance of developing and disseminating patient-centric, clinical practice guidelines that health care professionals can use to deliver COPD care. These will help primary care clinicians who are the providers of care to most people with COPD in rural areas, as these communities often lack pulmonologists.7 In rural settings, telehealth, telemedicine, telemonitoring, and telementoring can help relieve isolation, support appropriate education, and assist in patient care. Addressing reimbursement issues to support multidisciplinary team care to incentivize cost-effective interventions, such as pulmonary rehabilitation (PR), is also important. Additional resources available are the pocket guide based on the Global initiative for chronic Obstructive Lung Disease guidelines,8 and the COPD Foundation pocket guide and app.9 Electronic health records, such as those used in the VA's electronic health record (Vista/CPRS) system, also hold promise.10 Structured longitudinal telementoring of rural health care professionals, including medical assistants, respiratory therapists, and home health care professionals, could create a virtual "community of practice" that would facilitate COPD team management in rural areas. The strategy of "moving knowledge" instead of "moving patients" has been shown to be effective in managing other chronic diseases in medically underserved areas using the Extension for Community Health Outcomes model for telementoring.11, 12 Many rural areas have been federally designated as medically underserved in part because primary care there is provided by other health professionals, including nurse practitioners and physician assistants.13 Increasing the availability of other professionals, such as respiratory therapists, would provide important services to patients and families affected by COPD such as training in the use of inhalers,14 and delivery of PR, which improves patient clinical COPD outcomes but requires continued physical activity after initial program completion.15 These therapies are underutilized due to insufficient funding, resources, and reimbursement but also lack of awareness and knowledge by health care professionals, payors, and patients,15 and their delivery is often complicated by the long distances that rural COPD patients must travel to access them.16 Programs such as the Appalachian Pulmonary Health Project offer an example of successful delivery of a comprehensive outpatient PR in rural settings.17 PR structures also offer the opportunity to deliver tobacco cessation interventions and pulmonary function testing such as spirometry, which plays a necessary role in the diagnosis and assessment of severity of COPD.18 Potential alternatives, such as rehabilitation at home or telehealth rehabilitation with remote online supervision, are currently being tested.19 Goal 3 of the CNAP stresses the importance of delivering interventions based on evidence from the regions and populations to be served. Access to timely, comprehensive COPD data is foundational to identifying where to best target resources for rural patients' and health care providers' education, worksite wellness programs, and prevention programs, and to reduce disease burden. Although national COPD data are available, most rural-specific data are not easily accessible at the local level. In addition, because the Centers for Disease Control and Prevention (CDC) does not fund COPD programs, state and local public health departments have no local CDC-generated data to use. An alternative source for gathering COPD data in rural communities is through accountable care organizations (ACOs).20, 21 Because COPD-related health care costs due to disease flare-ups are very high (e.g., they require more ED visits, hospital admissions, and readmissions), ACOs are demonstrating that it is cost effective to monitor and manage COPD to prevent or minimize acute episodes. The ACO data that are used to monitor COPD care and patients' outcomes could be aggregated to support collaborative efforts in rural communities. Existing annual databases can also provide rural data on COPD. Public access to http://wonder.cdc.gov provides annual death certificate information from the National Vital Statistics System, run by the National Center for Health Statistics. County-level prevalence of COPD and other chronic conditions among annual Medicare fee-for-service enrollees may be accessed at http://www.cms.gov. Urban-rural categories data can be analyzed using the Federal Information Processing Specification county code.22 Address locations of providers and specialists who submit Medicare and Medicaid claims may be obtained from the National Provider Identifier Registry (http://www.cms.gov). Self-reported doctor-diagnosed COPD, other chronic diseases, risk factors, and sociodemographic characteristics from the annual Behavioral Risk Factor Surveillance System may be obtained at www.cdc.gov/brfss and www.cdc.gov/cdi. To facilitate the analysis and use of these fragmented data sources, it is imperative to continue to create accessible linkages to the rural communities, and a CDC data portal with downloadable county-level COPD data would be useful for promoting rural efforts. Goal 4 of the CNAP aims at fostering all aspects of COPD research. For example, cigarette smoking is a prime target for intervention not only because it is responsible for 75% of COPD cases nationally, but also because it disproportionately impacts rural residents.23 Less access to public education programs that teach the dangers of smoking and its connection with COPD must be corrected through the implementation of tobacco use prevention and cessation programs.24, 25 Additionally, up to 25% of patients with COPD report having never smoked,26 and data collected from these individuals identify occupational and environmental exposures such as passive smoke, biomass fuels used for cooking and heating, mining dusts, or agricultural biodusts.26 Research is needed to further clarify the roles of additional agents as possible causes of airflow obstruction and lung tissue damage and to document the effectiveness of exposure reduction strategies in preventing COPD.27-29 To this end, the participation of individuals from rural communities in registries and clinical trials conducted in rural settings is key to delivering meaningful results. Research on evidence-based models for preventing, diagnosing, and treating COPD in rural practices can be facilitated, for example, through partnerships between COPD researchers and Primary Care Practice-based Research Networks (PBRNs).30 Currently, 5 PBRNs are participating in the NHLBI-funded CAPTURE COPD study aimed at validating the sensitivity, specificity, and predictive value of a 5-item survey and a peak expiratory flow measurement to identify patients with undiagnosed, clinically significant COPD.31 Additional opportunities to facilitate and enhance COPD research in rural settings could stem from public-private partnerships, including those with industry, and the use of different models of diagnostic and therapeutic delivery. Text message-based smoking cessation interventions are effective and can be beneficial for rural residents,32 and telemedicine is an attractive option for providing COPD care to rural patients.33 PR, including home-based PR, could also be delivered through telehealth.19, 34 Local health care professionals and national patient advocacy groups could help increase participation of rural residents in research and clinical trials.35 Goal 5 calls for implementation of the CNAP, including in rural settings, and translating national COPD strategies into state- and community-based initiatives. This requires a multipronged approach and sustained efforts from all interested parties. Federal agencies that provide health care-related grants to states, such as NIH, HRSA, CDC, Patient-Centered Outcomes Research Institute, the Agency for Healthcare Research and Quality, the US Department of Agriculture, and others, must integrate COPD into their programs, and they need to fully engage state governments and agencies in COPD initiatives. In turn, states could be required or incentivized to engage in interagency collaborations to address COPD. Barriers to collaboration need to be removed to facilitate partnerships, including those with drug and device industries. These stipulations must be reflected in funding announcements, along with the economic, cultural, social, geographic, and demographic characteristics of rural communities. Rural patients could be organized around local chapters of national support groups, such as the ALA Better Breathers Clubs, the COPD Foundation State Captains and Harmonicas for Health, and other groups sponsored by existing trusted partners. State and federal health services agencies could educate and engage existing health and social service advocacy organizations (e.g., the NRHA, state rural health associations, state hospital associations, state offices of rural health, PCAs, county medical associations, and Community Action Agencies) to incorporate COPD in their messaging. Medicare Rural Hospital Flexibility grant funding could be leveraged to engage and track patients with COPD. State, local, and tribal health departments and organizations could prioritize COPD education and referrals, and health centers could institute COPD measures in the set collected by Federally Qualified Health Centers and Rural Health Clinics. Notably, a demonstrated return on investment (ROI) could pave the way for increased job opportunities in rural settings (e.g., for respiratory therapists, nurses, pharmacists, community health workers, physician assistants). Finally, organizations such as the National Governors Association and the National Conference of State Legislatures should recognize the significance of COPD, encourage governors and state legislators to pass legislation that addresses the disease, and ensure that each state has a well-articulated COPD plan that outlines specific strategies, including those addressing workforce shortages. COPD is a common, underdiagnosed, undertreated, and devastating chronic lung disease prevalently affecting underserved communities such as those of rural America. A concerted effort from all interested parties will make a difference in the lives of people and families affected by COPD and the communities in which they live.

The National Heart, Lung, and Blood Institute (NHLBI) provides global leadership for a research, training, and education program to promote the prevention and treatment of heart, lung, and blood diseases and enhance the health of all individuals so that they can live longer and more fulfilling lives. Inherent in this mission is the commitment to advance health equity research as an avenue for enhancing the health of all individuals. Additionally, the four goals and eight research objectives of the NHLBI Strategic Vision directly support the commitment to health equity. In this article, we present selected examples of the NHLBI Strategic Vision implementation approaches for advancing health equity research in our mission areas of heart, lung, and blood diseases. Examples of diseases for which the burden of health inequities and our strategic vision implementation approaches are discussed include hypertension, heart failure, vascular dementia, asthma, and sickle cell disease. Examples are provided of new avenues of Institute-solicited research to stimulate and address compelling scientific questions and critical challenges to advance health equity. We also highlight the emerging fields of implementation science and predictive analytics as important opportunities to accelerate the translation of discovery science into health impact for all and to advance health equity.

Personalized medicine is not new. For centuries physicians have provided individualized care based on the nuanced clinical presentations of patients and the severity of their diseases. However, analytical advances over the past decade have sparked a hope that we may soon be able to deliver medical care with unprecedented resolution and effectiveness. To distinguish that new era of personalized medicine from the kind practiced by Galen in ancient Rome, a new term has been coined. Precision medicine describes a molecule-based approach to personalized medicine, one that can use precise biological measures (biomarker assays, genetic and epigenetic information, imaging studies, and quantitative clinical phenotypes) to determine the right treatment for the right patient at the right time. Analogous opportunities exist for precise prevention. Here come the omics!Annals of Allergy, Asthma & ImmunologyVol. 123Issue 6PreviewA long-term goal of clinical care has always been to fit the specific treatment to the individual patient—what we would now call personalized medicine. However, the ability to predict which patient will best respond to which treatment has historically been nearly impossible. Accordingly, personalized medicine has typically involved significant trial and error with different therapies until desired clinical results are achieved. Fortunately for both patients and physicians, this paradigm has begun to change. Full-Text PDF

The NHLBI’s DLD oversees research programs encompassing numerous rare lung diseases and is firmly committed to supporting research across the spectrum of basic science to clinical observational studies and interventional trials conducted by investigators at all career stages. Although most rare lung diseases research funded by the DLD stems from investigator-initiated applications in response to parent funding opportunity announcements, several successful institute-initiated rare lung diseases research programs demonstrate the DLD’s sustained commitment toward improving outcomes in rare lung diseases. With the promise of exciting technologic advances, the existence of novel funding opportunities for a cadre of skilled investigators, and the collaborative efforts of relevant advocacy groups and consortia, the goal to accelerate scientific research and improve outcomes in rare lung diseases is being realized.

Limb girdle muscular dystrophy type 2A (LGMD2A), caused by mutations in the Calpain 3 (CAPN3) gene, is an incurable autosomal recessive disorder that results in muscle wasting and loss of ambulation. To test the feasibility of an autologous induced pluripotent stem cell (iPSC)-based therapy for LGMD2A, here we applied CRISPR-Cas9-mediated genome editing to iPSCs from three LGMD2A patients to enable correction of mutations in the CAPN3 gene. Using a gene knockin approach, we genome edited iPSCs carrying three different CAPN3 mutations, and we demonstrated the rescue of CAPN3 protein in myotube derivatives in vitro. Transplantation of gene-corrected LGMD2A myogenic progenitors in a novel mouse model combining immunodeficiency and a lack of CAPN3 resulted in muscle engraftment and rescue of the CAPN3 mRNA. Thus, we provide here proof of concept for the integration of genome editing and iPSC technologies to develop a novel autologous cell therapy for LGMD2A.

Targeted differentiation of pluripotent stem (PS) cells into myotubes enables in vitro disease modeling of skeletal muscle diseases. Although various protocols achieve myogenic differentiation in vitro, resulting myotubes typically display an embryonic identity. This is a major hurdle for accurately recapitulating disease phenotypes in vitro, as disease commonly manifests at later stages of development. To address this problem, we identified four factors from a small molecule screen whose combinatorial treatment resulted in myotubes with enhanced maturation, as shown by the expression profile of myosin heavy chain isoforms, as well as the upregulation of genes related with muscle contractile function. These molecular changes were confirmed by global chromatin accessibility and transcriptome studies. Importantly, we also observed this maturation in three-dimensional muscle constructs, which displayed improved in vitro contractile force generation in response to electrical stimulus. Thus, we established a model for in vitro muscle maturation from PS cells.

Asthma is the most prevalent chronic respiratory disease worldwide. Its increasing prevalence and evidence of suboptimal control require renewed efforts in the development and widespread implementation of clinical practice guidelines for prevention, treatment, and control. Given the rapidly changing landscape and evolving best practices for guideline development, the National Heart, Lung, and Blood Institute made a commitment to support rigorous systematic evidence reviews that frontline health care providers and stakeholders could use to create new or update existing guidelines. This article describes the protocols, key questions, methodology, and analytic framework to support the update of the 2007 National Asthma Education and Prevention Program Expert Panel Report 3 (EPR-3) on the diagnosis and management of asthma in adults and children. It also describes the expert panel's practical experience in managing asthmatic patients across the age and severity spectrum. The article explains the process for ensuring that the expert panel's deliberations are conducted in accordance with the Institute of Medicine's standards and recommendations for guideline development. The outcome of this ambitious effort will be an update of the EPR-3 asthma guidelines and publication of the key recommendations in the Journal of Allergy and Clinical Immunology. Importantly, several novel approaches will be explored and incorporated as appropriate to accelerate adoption and sustained implementation of the guidelines.

The Global Alliance against Chronic Respiratory Diseases (GARD) is a voluntary network of national and international organizations, institutions and agencies led by the World Health Organization (WHO), working towards the vision of a world where all people breathe freely (1). GARD is supporting WHO in successfully implementing the WHO’s Global Action Plan for the Prevention and Control of Noncommunicable Diseases (NCDs) 2013-2020. The GARD report on GARD activities is published on a regular basis. Collaboration among GARD countries is critical for sharing experiences and providing technical assistance to developing countries based on each country’s needs (2).