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Pulmonary neuroendocrine cells (PNECs) are unique airway epithelial cells that blend neuronal and endocrine functions, acting as key sensors in the lung. They respond to environmental stimuli like allergens by releasing neuropeptides and neurotransmitters. PNECs stand out as the only lung epithelial cells innervated by neurons, suggesting a significant role in airway-nerve communication via direct neural pathways and hormone release. Pathological conditions such as asthma are linked to increased PNECs counts and elevated calcitonin gene-related peptide (CGRP) production, which may affect neuroprotection and brain function. CGRP is also associated with neurodegenerative diseases, including Parkinson's and Alzheimer's, potentially due to its influence on inflammation and cholinergic activity. Despite their low numbers, PNECs are crucial for a wide range of functions, highlighting the importance of further research. Advances in technology for producing and culturing human PNECs enable the exploration of new mechanisms and cell-specific responses to targeted therapies for PNEC-focused treatments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Thakur, Mei, Zhang, Zhang, Taslakjian, Lian, Wu, Chen, Solway and Chen.)

Background: Increasing functional residual capacity (FRC) or tidal volume (V T ) reduces airway resistance and attenuates the response to bronchoconstrictor stimuli in animals and humans. What is unknown is which one of the above mechanisms is more effective in modulating airway caliber and whether their combination yields additive or synergistic effects. To address this question, we investigated the effects of increased FRC and increased V T in attenuating the bronchoconstriction induced by inhaled methacholine (MCh) in healthy humans., Methods: Nineteen healthy volunteers were challenged with a single-dose of MCh and forced oscillation was used to measure inspiratory resistance at 5 and 19 Hz (R 5 and R 19 ), their difference (R 5-19 ), and reactance at 5 Hz (X 5 ) during spontaneous breathing and during imposed breathing patterns with increased FRC, or V T , or both. Importantly, in our experimental design we held the product of V T and breathing frequency (BF), i.e, minute ventilation (V E ) fixed so as to better isolate the effects of changes in V T alone., Results: Tripling V T from baseline FRC significantly attenuated the effects of MCh on R 5 , R 19 , R 5-19 and X 5 . Doubling V T while halving BF had insignificant effects. Increasing FRC by either one or two V T significantly attenuated the effects of MCh on R 5, R 19 , R 5-19 and X 5 . Increasing both V T and FRC had additive effects on R 5 , R 19 , R 5-19 and X 5 , but the effect of increasing FRC was more consistent than increasing V T thus suggesting larger bronchodilation. When compared at iso-volume, there were no differences among breathing patterns with the exception of when V T was three times larger than during spontaneous breathing., Conclusions: These data show that increasing FRC and V T can attenuate induced bronchoconstriction in healthy humans by additive effects that are mainly related to an increase of mean operational lung volume. We suggest that static stretching as with increasing FRC is more effective than tidal stretching at constant V E , possibly through a combination of effects on airway geometry and airway smooth muscle dynamics., (© 2024. The Author(s).)

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by progressive scarring of the lungs and resulting in deterioration in lung function. Transforming growth factor-β (TGF-β) is one of the most established drivers of fibrotic processes. TGF-β promotes the transformation of tissue fibroblasts to myofibroblasts, a key finding in the pathogenesis of pulmonary fibrosis. We report here that TGF-β robustly upregulates the expression of the calcium-activated chloride channel anoctamin-1 (ANO1) in human lung fibroblasts (HLFs) at mRNA and protein levels. ANO1 is readily detected in fibrotic areas of IPF lungs in the same area with smooth muscle α-actin (SMA)-positive myofibroblasts. TGF-β-induced myofibroblast differentiation (determined by the expression of SMA, collagen-1, and fibronectin) is significantly inhibited by a specific ANO1 inhibitor, T16A inh -A01, or by siRNA-mediated ANO1 knockdown. T16A inh -A01 and ANO1 siRNA attenuate profibrotic TGF-β signaling, including activation of RhoA pathway and AKT, without affecting initial Smad2 phosphorylation. Mechanistically, TGF-β treatment of HLFs results in a significant increase in intracellular chloride levels, which is prevented by T16A inh -A01 or by ANO1 knockdown. The downstream mechanism involves the chloride-sensing "with-no-lysine (K)" kinase (WNK1). WNK1 siRNA significantly attenuates TGF-β-induced myofibroblast differentiation and signaling (RhoA pathway and AKT), whereas the WNK1 kinase inhibitor WNK463 is largely ineffective. Together, these data demonstrate that 1 ) ANO1 is a TGF-β-inducible chloride channel that contributes to increased intracellular chloride concentration in response to TGF-β; and 2 ) ANO1 mediates TGF-β-induced myofibroblast differentiation and fibrotic signaling in a manner dependent on WNK1 protein but independent of WNK1 kinase activity. NEW & NOTEWORTHY This study describes a novel mechanism of differentiation of human lung fibroblasts (HLFs) to myofibroblasts: the key process in the pathogenesis of pulmonary fibrosis. Transforming growth factor-β (TGF-β) drives the expression of calcium-activated chloride channel anoctmin-1 (ANO1) leading to an increase in intracellular levels of chloride. The latter recruits chloride-sensitive with-no-lysine (K) kinase (WNK1) to activate profibrotic RhoA and AKT signaling pathways, possibly through activation of mammalian target of rapamycin complex-2 (mTORC2), altogether promoting myofibroblast differentiation.

Stress and diabetes coexist in a vicious cycle. Different types of stress lead to diabetes, while diabetes itself is a major life stressor. This was the focus of the Chicago Biomedical Consortium's 19 th annual symposium, "Stress and Human Health: Diabetes," in November 2022. There, researchers primarily from the Chicago area met to explore how different sources of stress - from the cells to the community - impact diabetes outcomes. Presenters discussed the consequences of stress arising from mutant proteins, obesity, sleep disturbances, environmental pollutants, COVID-19, and racial and socioeconomic disparities. This symposium showcased the latest diabetes research and highlighted promising new treatment approaches for mitigating stress in diabetes., Competing Interests: RMS declares that he has received honoraria from CVS/Health and the American Medical Forum; neither of which relate this manuscript. SAO is a co-founder, equity holder, and consultant for OptiKIRA, LLC. All other authors have no competing interests to declare., (© The Author(s) 2023.)

The National COVID Cohort Collaborative (N3C) is a public-private-government partnership established during the Coronavirus pandemic to create a centralized data resource called the "N3C data enclave." This resource contains individual-level health data from participating healthcare sites nationwide to support rapid collaborative analytics. N3C has enabled analytics within a cloud-based enclave of data from electronic health records from over 17 million people (with and without COVID-19) in the USA. To achieve this goal of a shared data resource, N3C implemented a shared governance strategy involving stakeholders in decision-making. The approach leveraged best practices in data stewardship and team science to rapidly enable COVID-19-related research at scale while respecting the privacy of data subjects and participating institutions. N3C balanced equitable access to data, team-based scientific productivity, and individual professional recognition - a key incentive for academic researchers. This governance approach makes N3C research sustainable and effective beyond the initial days of the pandemic. N3C demonstrated that shared governance can overcome traditional barriers to data sharing without compromising data security and trust. The governance innovations described herein are a helpful framework for other privacy-preserving data infrastructure programs and provide a working model for effective team science beyond COVID-19., Competing Interests: None of the authors has conflicts of interest related to this work., (© The Author(s) 2023.)

Background/objective: Non-clinical aspects of life, such as social, environmental, behavioral, psychological, and economic factors, what we call the sociome, play significant roles in shaping patient health and health outcomes. This paper introduces the Sociome Data Commons (SDC), a new research platform that enables large-scale data analysis for investigating such factors., Methods: This platform focuses on "hyper-local" data, i.e., at the neighborhood or point level, a geospatial scale of data not adequately considered in existing tools and projects. We enumerate key insights gained regarding data quality standards, data governance, and organizational structure for long-term project sustainability. A pilot use case investigating sociome factors associated with asthma exacerbations in children residing on the South Side of Chicago used machine learning and six SDC datasets., Results: The pilot use case reveals one dominant spatial cluster for asthma exacerbations and important roles of housing conditions and cost, proximity to Superfund pollution sites, urban flooding, violent crime, lack of insurance, and a poverty index., Conclusion: The SDC has been purposefully designed to support and encourage extension of the platform into new data sets as well as the continued development, refinement, and adoption of standards for dataset quality, dataset inclusion, metadata annotation, and data access/governance. The asthma pilot has served as the first driver use case and demonstrates promise for future investigation into the sociome and clinical outcomes. Additional projects will be selected, in part for their ability to exercise and grow the capacity of the SDC to meet its ambitious goals., Competing Interests: S.N. served on an advisory board for Avillion/Astra Zeneca, receives royalties from Wolters-Kluwer and Springer, and research funding from NIH and Asthma Allergy Foundation of America. C.S. served on advisory boards for Gilead and Merck, receives royalties from Wolters-Kluwer, and research funding from CDC. A.S. Holds voluntary positions in the American Medical Informatics Association and is an equity investor in healthcare companies and other industries. J.S. reports a potential financial interest in PulmOne Advanced Medical Devices, Ltd, Israel, and research grant funding from NIH, NSF, and Respiratory Health Association of Metropolitan Chicago. S.V. is co-founder and Chief Medical Officer for Litmus Health, Inc., and receives consulting royalties from CVS Accordant., (© The Author(s) 2023.)

Competing Interests: RB, TJB, VZ, HZ, AES, and RK have nothing to disclose. AA has received speaking and advisory board fees from Genentech and Boehringer Ingelheim and is supported by a career development award from the National Heart, Lung, and Blood Institute (NHLBI K23HL146942), and grant funding from the American College of Chest Physicians and the Pulmonary Fibrosis Foundation. BKP is supported by a career development award from the NHLBI (K23-HL148387) and funding from the Walder Foundation and the Center for Healthcare Delivery Science and Innovation at the University of Chicago. WFP is supported by a career development award from the NHLBI (K08HL150291). JS has research and training funding from NIH, NSF, and the Burroughs Wellcome Fund, and has a potential financial interest in PulmOne Advanced Medical Diagnostics, Ltd, Israel. AES has equities in the following companies: Pharmaceuticals: Abbott Laboratories, Pfizer, Novo Nordisk. Industrials: in construction, IT, finance, retail, and food sectors (21 companies and 2 exchange traded funds).

Background: Pulmonary fibrosis is characterized by lung parenchymal destruction and can increase morbidity and mortality. Pulmonary fibrosis commonly occurs following hospitalization for SARS-CoV-2 infection. As there are medications that modify pulmonary fibrosis risk, we investigated whether distinct pharmacotherapies (amiodarone, cancer chemotherapy, corticosteroids, and rituximab) are associated with differences in post-COVID-19 pulmonary fibrosis incidence., Methods: We used the National COVID-19 Cohort Collaboration (N3C) Data Enclave, which aggregates and harmonizes COVID-19 data across the United States, to assess pulmonary fibrosis incidence documented at least 60 days after COVID-19 diagnosis among adults hospitalized between January 1st, 2020 and July 6th, 2022 without pre-existing pulmonary fibrosis. We used propensity scores to match pre-COVID-19 drug-exposed and unexposed cohorts (1:1) based on covariates with known influence on pulmonary fibrosis incidence, and estimated the association of drug exposure with risk for post-COVID-19 pulmonary fibrosis. Sensitivity analyses considered pulmonary fibrosis incidence documented at least 30- or 90-days post-hospitalization and pulmonary fibrosis incidence in the COVID-19-negative N3C population., Findings: Among 5,923,394 patients with COVID-19, we analyzed 452,951 hospitalized adults, among whom pulmonary fibrosis incidence was 1.1 per 100-person-years. 277,984 hospitalized adults with COVID-19 were included in our primary analysis, among whom all drug exposed cohorts were well-matched to unexposed cohorts (standardized mean differences <0.1). The post-COVID-19 pulmonary fibrosis incidence rate ratio (IRR) was 2.5 (95% CI 1.2-5.1, P = 0.01) for rituximab, 1.6 (95% CI 1.3-2.0, P < 0.0001) for chemotherapy, and 1.2 (95% CI 1.0-1.3, P = 0.02) for corticosteroids. Amiodarone exposure had no significant association with post-COVID-19 pulmonary fibrosis (IRR = 0.8, 95% CI 0.6-1.1, P = 0.24). In sensitivity analyses, pre-COVID-19 corticosteroid use was not consistently associated with post-COVID-19 pulmonary fibrosis. In the COVID-19 negative hospitalized population (n = 1,240,461), pulmonary fibrosis incidence was lower overall (0.6 per 100-person-years) and for patients exposed to all four drugs., Interpretation: Recent rituximab or cancer chemotherapy before COVID-19 infection in hospitalized patients is associated with increased risk for post-COVID-19 pulmonary fibrosis., Funding: The analyses described in this publication were conducted with data or tools accessed through the NCATS N3C Data Enclave https://covid.cd2h.org and N3C Attribution & Publication Policy v1.2-2020-08-25b supported by NIHK23HL146942, NIHK08HL150291, NIHK23HL148387, NIHUL1TR002389, NCATSU24 TR002306, and a SECURED grant from the Walder Foundation/Center for Healthcare Delivery Science and Innovation, University of Chicago. WFP received a grant from the Greenwall Foundation. This research was possible because of the patients whose information is included within the data and the organizations (https://ncats.nih.gov/n3c/resources/data-contribution/data-transfer-agreement-signatories) and scientists who have contributed to the on-going development of this community resource (https://doi.org/10.1093/jamia/ocaa196)., Competing Interests: RB, TJB, VZ, HZ, AES, and RK have nothing to disclose. AA has received speaking and advisory board fees from Genentech and Boehringer Ingelheim and is supported by a career development award from the National Heart, Lung, and Blood Institute (NHLBI K23HL146942), and grant funding from the American College of Chest Physicians and the Pulmonary Fibrosis Foundation. BKP is supported by a career development award from the NHLBI (K23-HL148387) and funding from the Walder Foundation and the Center for Healthcare Delivery Science and Innovation at the University of Chicago. JS has research and training funding from NIH, NSF, and the Burroughs Wellcome Fund, and has a potential financial interest in PulmOne Advanced Medical Diagnostics, Ltd, Israel., (© 2023 The Author(s).)

Asthma is a heterogeneous, complex syndrome, and identifying asthma endotypes has been challenging. We hypothesize that distinct endotypes of asthma arise in disparate genetic variation and life-time environmental exposure backgrounds, and that disease comorbidity patterns serve as a surrogate for such genetic and exposure variations. Here, we computationally discover 22 distinct comorbid disease patterns among individuals with asthma (asthma comorbidity subgroups) using diagnosis records for >151 M US residents, and re-identify 11 of the 22 subgroups in the much smaller UK Biobank. GWASs to discern asthma risk loci for individuals within each subgroup and in all subgroups combined reveal 109 independent risk loci, of which 52 are replicated in multi-ancestry meta-analysis across different ethnicity subsamples in UK Biobank, US BioVU, and BioBank Japan. Fourteen loci confer asthma risk in multiple subgroups and in all subgroups combined. Importantly, another six loci confer asthma risk in only one subgroup. The strength of association between asthma and each of 44 health-related phenotypes also varies dramatically across subgroups. This work reveals subpopulations of asthma patients distinguished by comorbidity patterns, asthma risk loci, gene expression, and health-related phenotypes, and so reveals different asthma endotypes., (© 2022. The Author(s).)

Background: Pharmacogenetic studies in asthma cohorts, primarily made up of White people of European descent, have identified loci associated with response to inhaled beta agonists and corticosteroids (ICSs). Differences exist in how individuals from different ancestral backgrounds respond to long-acting beta agonist (LABA) and ICSs. Therefore, we sought to understand the pharmacogenetic mechanisms regulating therapeutic responsiveness in individuals of African descent., Methods: We did ancestry-based pharmacogenetic studies of children (aged 5-11 years) and adolescents and adults (aged 12-69 years) from the Best African Response to Drug (BARD) trials, in which participants with asthma uncontrolled with low-dose ICS (fluticasone propionate 50 μg in children, 100 μg in adolescents and adults) received different step-up combination therapies. The hierarchal composite outcome of pairwise superior responsiveness in BARD was based on asthma exacerbations, a 31-day difference in annualised asthma-control days, or a 5% difference in percentage predicted FEV 1 . We did whole-genome admixture mapping of 15 159 ancestral segments within 312 independent regions, stratified by the two age groups. The two co-primary outcome comparisons were the step up from low-dose ICS to the quintuple dose of ICS (5 × ICS: 250 μg twice daily in children and 500 μg twice daily in adolescents and adults) versus double dose (2-2·5 × ICS: 100 μg twice daily in children, 250 μg twice daily in adolescents and adults), and 5 × ICS versus 100 μg fluticasone plus a LABA (salmeterol 50 μg twice daily). We used a genome-wide significance threshold of p<1·6 × 10 -4 , and tested for replication using independent cohorts of individuals of African descent with asthma., Findings: We included 249 unrelated children and 267 unrelated adolescents and adults in the BARD pharmacogenetic analysis. In children, we identified a significant admixture mapping peak for superior responsiveness to 5 × ICS versus 100 μg fluticasone plus salmeterol on chromosome 12 (odds ratio [OR local African ] 3·95, 95% CI 2·02-7·72, p=6·1 × 10 -5 ) fine mapped to a locus adjacent to RNFT2 and NOS1 (rs73399224, OR allele dose 0·17, 95% CI 0·07-0·42, p=8·4 × 10 -5 ). In adolescents and adults, we identified a peak for superior responsiveness to 5 × ICS versus 2·5 × ICS on chromosome 22 (OR local African 3·35, 1·98-5·67, p=6·8 × 10 -6 ) containing a locus adjacent to TPST2 (rs5752429, OR allele dose 0·21, 0·09-0·52, p=5·7 × 10 -4 ). We replicated rs5752429 and nominally replicated rs73399224 in independent African American cohorts., Interpretation: BARD is the first genome-wide pharmacogenetic study of LABA and ICS response in clinical trials of individuals of African descent to detect and replicate genome-wide significant loci. Admixture mapping of the composite BARD trial outcome enabled the identification of novel pharmacogenetic variation accounting for differential therapeutic responses in people of African descent with asthma., Funding: National Institutes of Health, National Heart, Lung, and Blood Institute., Competing Interests: Declaration of interests VEO reports consulting fees from Sanofi and fees for serving on independent data monitoring committees for Sanofi and Regeneron Pharmaceuticals. SJS reports receiving consulting fees, paid to his institution, from AstraZeneca, GlaxoSmithKline, Moderna, Propeller Health, Regeneron, and Sanofi, as well as a research grant from Propeller Health. ERB reports receiving consulting fees and donated drugs from Boehringer Ingelheim, donated drugs from Merck and Teva Pharmaceuticals, consulting fees from AstraZeneca, MedImmune, GlaxoSmithKline, Novartis, and Sanofi–Regeneron, and participating in trials as an employee of Wake Forest School of Medicine and the University of Arizona for AstraZeneca, MedImmune, Boehringer Ingelheim, Cephalon–Teva Pharmaceuticals, Genentech, GlaxoSmithKline, Johnson & Johnson (Janssen), Novartis, and Sanofi–Regeneron. VMC reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. WP reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. DM reports receiving grant support and donated drugs from GlaxoSmithKline, Genentech, Vifor Pharma, Boehringer Ingelheim, and Teva Pharmaceuticals, grant support from Sanofi and AstraZeneca, fees for serving on a data and safety monitoring board from Novartis, and donated drugs from Merck. FDM reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals, grant support from Johnson & Johnson, and consulting fees from Copeval and Commence. EH-L reports a fellowship from the Spanish Ministry of Science, Innovation, and Universities. MP-Y reports grants from the Spanish Ministry of Economy, Industry, and Competitiveness, the State Research Agency and the European Regional Development Funds from the European Union (MICIU/AEI/FEDER, UE), and grant support from GlaxoSmithKline, Spain. SJK reports receiving donated drugs from Merck–Organon, Genentech, GlaxoSmithKline, and Regeneron and owning stock in Merck. LBB reports receiving consulting fees and lecture fees from Aerocrine, GlaxoSmithKline, Genentech–Novartis, and AstraZeneca, advisory board fees and donated drugs from Merck, fees for serving on a data safety monitoring board from DBV Technologies, consulting fees, lecture fees, and donated drugs from Teva Pharmaceuticals and Boehringer Ingelheim, honoraria from WebMD–Medscape, advisory board fees and lecture fees from Sanofi–Regeneron, advisory board fees and consulting fees from Vectura, and advisory board fees from Circassia. MDC reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals, and consulting fees from Genentech and Novartis. JCC reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. MC reports receiving grant support, lecture fees, and donated drugs from Boehringer Ingelheim, donated drugs from Merck, consulting fees, lecture fees, and donated drugs from Teva Pharmaceuticals, consulting fees and lecture fees from Boston Scientific and Genentech, consulting fees from Nuvaira, Aviragen, 4D Pharma, VIDA Diagnostics, Mallinckrodt Pharmaceuticals, Theravance, Therabron, and Vectura, grant support, consulting fees, and lecture fees from Sanofi-Aventis, grant support and lecture fees from AstraZeneca and GlaxoSmithKline, grant support from Chiesi and Novartis, and lecture fees from Regeneron Pharmaceuticals. LCD reports receiving grant support and consulting fees from AstraZeneca, and consulting fees from Sanofi–Regeneron. FH reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. DJJ reports grant support from GlaxoSmithKline, consulting fees from Novartis, Sanofi, Regeneron, Vifor Pharma, and AstraZeneca, and fees for serving on a data and safety monitoring board from Pfizer. NJ reports receiving honorarium for consulting from GlaxoSmithKline pharmaceuticals and Pulmocide. MK reports receiving grant support from Chiesi and Sanofi. JAK reports personal fees for independent data monitoring committee participation from Sanofi and research funding from the American Lung Association—Airway Clinical Research Centers Network. SCL reports grant funding from the American Lung Association—Airway Clinical Research Centers Network. RFL reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals, and lecture fees from Thermo Fisher Scientific. JJL reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. NL reports receiving grant support, advisory board fees, and donated drugs from GlaxoSmithKline, grant support, consulting fees, and advisory board fees from AstraZeneca, consulting fees, advisory board fees, and donated drugs from Teva Pharmaceuticals, grant support from Genentech, grant support and advisory board fees from Sanofi–Regeneron, and donated drugs from Merck and Boehringer Ingelheim. WCM reports receiving grant support and donated drugs from Boehringer Ingelheim, donated drugs from Merck and Teva Pharmaceuticals, grant support and advisory board fees from AstraZeneca, GlaxoSmithKline, and Sanofi–Regeneron, and grant support from Novartis, Cumberland Pharmaceuticals, and Gossamer Bio. SPP reports receiving advisory board fees from AstraZeneca, GlaxoSmithKline, Mylan, Teva Pharmaceuticals, Sanofi–Regeneron, and Theravance, fees for serving as clinical trial adjudicator from Quintiles, fees for serving on a data and safety monitoring board from Genentech, fees for serving as chair of a data and safety monitoring board from Novartis, and honoraria from PRIME. JAP reports receiving donated drugs from Boehringer Ingelheim, Merck, Teva Pharmaceuticals, and GlaxoSmithKline. LJS reports receiving donated drugs from Boehringer Ingelheim and Teva Pharmaceuticals, and fees for serving on a data and safety monitoring board and donated drugs from Merck. JS reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals, advisory board fees from PulmOne Advanced Medical Devices, advisory board fees, honoraria, and travel support from Regeneron–Sanofi–Genzyme, holding patents #6 090 618, #6 114 311, #6 284 743, #6 291 211, #6 297 221, #6 331 527, and #7 169 764 on a smooth-muscle gene promoter (SM22 alpha), holding pending patent PCT/US2014/032186 on a method for determining respiratory physiological parameters, holding pending patent 62/872,980 on remodilins for airway remodelling and organ fibrosis, and holding pending patent 62/828,122 on remodilins to prevent or treat cancer metastasis, glaucoma, and hypoxia. CAS reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. SW reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals, grant support and consulting fees from AstraZeneca and Sanofi, and consulting fees from Pieris Pharmaceuticals. DAM reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. EI reports receiving grant support and consulting fees from AstraZeneca, Novartis, and Genentech, consulting fees from Regeneron Pharmaceuticals, Bird Rock Bio, Nuvelution Pharmaceuticals, Vitaeris, Sanofi Genzyme, Entrinsic Health Solutions, Pneuma Respiratory, 4D Pharma, Sienna Biopharmaceuticals, and Equillium, grant support, consulting fees, and donated drugs from Merck, Teva Pharmaceutical Industries, and GlaxoSmithKline, serving as a consultant for Vorso, receiving grant support and donated drugs from Vifor Pharma, Boehringer Ingelheim, and Teva Pharmaceuticals, grant support from Sanofi and AstraZeneca, and donated drugs from Circassia. MEW reports receiving grant support and consulting fees from AstraZeneca, Novartis, Sanofi, and GlaxoSmithKline, consulting fees from Regeneron Pharmaceuticals, Mylan, Genentech, Restorbio, Equillium, Boston Scientific, Genzyme, Gala Therapeutics, and Pulmatrix, fees for serving on a data and safety monitoring board from Sentien Biotechnologies, grant support, consulting fees, advisory board fees, and donated drugs from Teva Pharmaceuticals, consulting fees and donated drugs from Boehringer Ingelheim and Merck. MD, GAH, EJA CC, CE, AMF, DH, AM, ETN, SPS, MAS, SRW, EGB, and KB declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Numerous publications describe the clinical manifestations of post-acute sequelae of SARS-CoV-2 (PASC or "long COVID"), but they are difficult to integrate because of heterogeneous methods and the lack of a standard for denoting the many phenotypic manifestations. Patient-led studies are of particular importance for understanding the natural history of COVID-19, but integration is hampered because they often use different terms to describe the same symptom or condition. This significant disparity in patient versus clinical characterization motivated the proposed ontological approach to specifying manifestations, which will improve capture and integration of future long COVID studies., Methods: The Human Phenotype Ontology (HPO) is a widely used standard for exchange and analysis of phenotypic abnormalities in human disease but has not yet been applied to the analysis of COVID-19., Funding: We identified 303 articles published before April 29, 2021, curated 59 relevant manuscripts that described clinical manifestations in 81 cohorts three weeks or more following acute COVID-19, and mapped 287 unique clinical findings to HPO terms. We present layperson synonyms and definitions that can be used to link patient self-report questionnaires to standard medical terminology. Long COVID clinical manifestations are not assessed consistently across studies, and most manifestations have been reported with a wide range of synonyms by different authors. Across at least 10 cohorts, authors reported 31 unique clinical features corresponding to HPO terms; the most commonly reported feature was Fatigue (median 45.1%) and the least commonly reported was Nausea (median 3.9%), but the reported percentages varied widely between studies., Interpretation: Translating long COVID manifestations into computable HPO terms will improve analysis, data capture, and classification of long COVID patients. If researchers, clinicians, and patients share a common language, then studies can be compared/pooled more effectively. Furthermore, mapping lay terminology to HPO will help patients assist clinicians and researchers in creating phenotypic characterizations that are computationally accessible, thereby improving the stratification, diagnosis, and treatment of long COVID., Funding: U24TR002306; UL1TR001439; P30AG024832; GBMF4552; R01HG010067; UL1TR002535; K23HL128909; UL1TR002389; K99GM145411., Competing Interests: Declaration of Competing Interest RRD, TDB, JBB, CGC, WBH, JAM, AMP, ERP, HMR, JS, RAS, AES, JS, GS, MAH, PNR report funding from NIH. MAH and JAM are co-founders of Pryzm Health., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Importance: Deficient (ie, <20 ng/mL) or insufficient (ie, 20 to <30 ng/mL) 25-hydroxyvitamin D (also known as calcifediol) levels are more common in Black individuals than White individuals and are associated with increased coronavirus disease 2019 (COVID-19) risk. Whether COVID-19 risk is associated with differences in vitamin D levels of 30 ng/mL or greater is not known., Objective: To examine whether COVID-19 test results are associated with differences in vitamin D levels of 30 ng/mL or greater, including for White individuals and for Black individuals., Design, Setting, and Participants: This retrospective cohort study was conducted at an academic medical center in Chicago, Illinois. Participants included individuals with data on vitamin D level within 365 days before COVID-19 testing, which was conducted from March 3 to December 30, 2020. Data were analyzed from September 11, 2020, to February 5, 2021., Exposures: The last vitamin D level before COVID-19 testing was categorized as less than 20 ng/mL (ie, deficient), 20 to less than 30 ng/mL (ie, insufficient), 30 to less than 40 ng/mL, or 40 ng/mL or greater. Treatment was defined by vitamin D type and dose 14 days before COVID-19 testing and treatment changes after last vitamin D level., Main Outcomes and Measures: The main outcome was a positive result for COVID-19 in polymerase chain reaction testing. Multivariable analyses tested whether previously measured vitamin D level was associated with having test results positive for COVID-19 in White individuals and in Black individuals, controlling for months and treatment changes since the vitamin D level was measured, as well as demographic characteristics and comorbidity indicators., Results: A total of 4638 individuals (mean [SD] age 52.8 [19.5] years; 3205 [69%] women) had data for a vitamin D level within 1 year before COVID-19 testing, including 2288 (49%) Black individuals, 1999 (43%) White individuals, and 351 individuals (8%) who were another race/ethnicity (eg, Asian, Mideast Indian, >1 race). Stratified by vitamin D level, 1251 individuals (27%) had less than 20 ng/mL, 1267 individuals (27%) had 20 to less than 30 ng/mL, 1023 individuals (22%) had 30 to less than 40 ng/mL, and 1097 individuals (24%) had 40 ng/mL or greater. Lower vitamin D levels were more common in Black individuals (<20 ng/mL: 829 of 2288 Black individuals [36%]) than White individuals (<20 ng/mL: 315 of 1999 White individuals [16%]). A total of 333 individuals (7%) had test results positive for COVID-19, including 102 White individuals (5%) and 211 Black individuals (9%). Multivariate analysis controlling for time since last vitamin D level measurement was used to estimate the outcomes associated with levels 14 days before COVID-19 testing. A positive test result for COVID-19 was not significantly associated with vitamin D levels in White individuals but was associated with vitamin D levels in Black individuals (compared with ≥40 ng/mL: <20 ng/mL incidence rate ratio [IRR], 2.55 [95% CI, 1.26-5.15]; P = .009; 20 to <30 ng/mL IRR, 1.69 [95% CI, 0.75-3.84]; P = .21; 30 to <40 ng/mL IRR, 2.64 [95% CI, 1.24-5.66]; P = .01). Stratified by vitamin D level, estimated COVID-19 positivity rates in Black individuals were 9.72% (95% CI, 6.74%-13.41%) for individuals with a vitamin D level less than 20 ng/mL, 6.47% (95% CI, 3.33%-10.28%) for individuals with a vitamin D level of 20 to less than 30 ng/mL, 10.10% (95% CI, 6.00%-15.47%) for individuals with a vitamin D level of 30 to less than 40 ng/mL, and 3.82% (95% CI, 1.78%-6.68%) for individuals with a vitamin D level of 40 ng/mL or higher. Multivariate analysis in individuals with a vitamin D level of 30 ng/mL or greater found that the IRR of a positive COVID-19 test result was 0.97 (95% CI, 0.94-0.99; P = .008) per 1-ng/mL increase in vitamin D overall and 0.95 (95% CI, 0.91-0.98; P = .003) per 1-ng/mL increase in vitamin D in Black individuals., Conclusions and Relevance: In this single-center retrospective cohort study, COVID-19 risk increased among Black individuals with vitamin D level less than 40 ng/mL compared with those with 40 ng/mL or greater and decreased with increasing levels among individuals with levels greater than 30 ng/mL. No significant associations were noted for White individuals. Randomized clinical trials should examine whether increasing vitamin D level to greater than 40 ng/mL affects COVID-19 risk.

Importance: Vitamin D treatment has been found to decrease the incidence of viral respiratory tract infection, especially in patients with vitamin D deficiency. Whether vitamin D is associated with coronavirus disease 2019 (COVID-19) incidence is unknown., Objective: To examine whether the last vitamin D status before COVID-19 testing is associated with COVID-19 test results., Design, Setting, and Participants: This retrospective cohort study at an urban academic medical center included patients with a 25-hydroxycholecalciferol or 1,25-dihydroxycholecalciferol level measured within 1 year before being tested for COVID-19 from March 3 to April 10, 2020., Exposures: Vitamin D deficiency was defined by the last measurement of 25-hydroxycholecalciferol less than 20 ng/mL or 1,25-dihydroxycholecalciferol less than 18 pg/mL before COVID-19 testing. Treatment changes were defined by changes in vitamin D type and dose between the date of the last vitamin D level measurement and the date of COVID-19 testing. Vitamin D deficiency and treatment changes were combined to categorize the most recent vitamin D status before COVID-19 testing as likely deficient (last level deficient and treatment not increased), likely sufficient (last level not deficient and treatment not decreased), and 2 groups with uncertain deficiency (last level deficient and treatment increased, and last level not deficient and treatment decreased)., Main Outcomes and Measures: The outcome was a positive COVID-19 polymerase chain reaction test result. Multivariable analysis tested whether vitamin D status before COVID-19 testing was associated with testing positive for COVID-19, controlling for demographic and comorbidity indicators., Results: A total of 489 patients (mean [SD] age, 49.2 [18.4] years; 366 [75%] women; and 331 [68%] race other than White) had a vitamin D level measured in the year before COVID-19 testing. Vitamin D status before COVID-19 testing was categorized as likely deficient for 124 participants (25%), likely sufficient for 287 (59%), and uncertain for 78 (16%). Overall, 71 participants (15%) tested positive for COVID-19. In multivariate analysis, testing positive for COVID-19 was associated with increasing age up to age 50 years (relative risk, 1.06; 95% CI, 1.01-1.09; P = .02); non-White race (relative risk, 2.54; 95% CI, 1.26-5.12; P = .009), and likely deficient vitamin D status (relative risk, 1.77; 95% CI, 1.12-2.81; P = .02) compared with likely sufficient vitamin D status. Predicted COVID-19 rates in the deficient group were 21.6% (95% CI, 14.0%-29.2%) vs 12.2%(95% CI, 8.9%-15.4%) in the sufficient group., Conclusions and Relevance: In this single-center, retrospective cohort study, likely deficient vitamin D status was associated with increased COVID-19 risk, a finding that suggests that randomized trials may be needed to determine whether vitamin D affects COVID-19 risk.

Background: A challenge in the post-GWAS era is to assign function to disease-associated variants. However, available resources do not include all tissues or environmental exposures that are relevant to all diseases. For example, exaggerated bronchoconstriction of airway smooth muscle cells (ASMCs) defines airway hyperresponsiveness (AHR), a cardinal feature of asthma. However, the contribution of ASMC to genetic and genomic studies has largely been overlooked. Our study aimed to address the gap in data availability from a critical tissue in genomic studies of asthma., Methods: We developed a cell model of AHR to discover variants associated with transcriptional, epigenetic, and cellular responses to two AHR promoting cytokines, IL-13 and IL-17A, and performed a GWAS of bronchial responsiveness (BRI) in humans., Results: Our study revealed significant response differences between ASMCs from asthma cases and controls, including genes implicated in asthma susceptibility. We defined molecular quantitative trait loci (QTLs) for expression (eQTLs) and methylation (meQTLs), and cellular QTLs for contractility (coQTLs) and performed a GWAS of BRI in human subjects. Variants in asthma GWAS were significantly enriched for ASM QTLs and BRI-associated SNPs, and near genes enriched for ASM function, many with small P values that did not reach stringent thresholds of significance in GWAS., Conclusions: Our study identified significant differences between ASMCs from asthma cases and controls, potentially reflecting trained tolerance in these cells, as well as a set of variants, overlooked in previous GWAS, which reflect the AHR component of asthma.

Global DNA hydroxymethylation mediated by the TET (ten-eleven translocation) enzyme was induced in allergen-induced airway hyperresponsiveness in mouse lung tissues and specifically in isolated airway smooth muscle (ASM) cells. TET is an α-ketoglutarate (α-KG)-dependent enzyme, and the production of α-KG is catalyzed by IDH (isocitrate dehydrogenase). However, the role of IDH in the regulation of DNA hydroxymethylation in ASM cells is unknown. In comparison with nonasthmatic cells, asthmatic ASM cells exhibited higher TET activity and IDH2 (but not IDH-1 or IDH-3 ) gene expression levels. We modified the expression of IDH2 in ASM cells from humans with asthma by siRNA and examined the α-KG levels, TET activity, global DNA hydroxymethylation, cell proliferation, and expression of ASM phenotypic genes. Inhibition of IDH2 in asthmatic ASM cells decreased the α-KG levels, TET activity, and global DNA hydroxymethylation, and reversed the aberrant ASM phenotypes (including decreased cell proliferation and ASM phenotypic gene expression). Specifically, asthmatic cells transfected with siRNA against IDH2 showed decreased 5hmC (5-hydroxymethylcytosine) levels at the TGFB2 (transforming growth factor-β2) promoter determined by oxidative bisulfite sequencing. Taken together, our findings reveal that IDH2 plays an important role in the epigenetic regulation of ASM phenotypic changes in asthmatic ASM cells, suggesting that IDH2 is a potential therapeutic target for reversing the abnormal phenotypes seen in asthma.

BACKGROUND: Previous studies have demonstrated that a whole-food, plant-based (WFPB) diet can aid in the prevention, and in some cases reversal, of some of the leading chronic diseases in the United States. The medical literature on the relationship between diet and disease is steadily growing. Over the last decade, the possible connection between diet and many dermatological conditions has been studied, including skin aging. OBJECTIVE: As patients are increasingly seeking dietary advice from their dermatologist related to preventing and reversing the aging of skin, dermatologists need an evidence-based approach to tackle this challenging topic. This review focuses on dietary factors that contribute to telomere length, a marker for cellular aging. Although various factors contribute to accelerating telomere shortening, this review focuses on dietary factors that contribute to telomere length, specifically gerontotoxins and antioxidants. These can be measured in the blood, making them biomarkers of accelerated cellular skin aging. Included in this discussion is an evidence-based approach to increase the amount of antioxidants and decrease the amount of gerontotoxins in the diet, resulting in healthier skin. METHODS: A comprehensive MEDLINE (PubMed) literature review search was performed. Keywords used included: WFPB, telomerase, coronary artery disease, cellular aging, cigarette smoke, photoaging, telomeres, antioxidants, gerontotoxins, intrinsic cutaneous aging, extrinsic cutaneous aging, advanced glycation end products (AGEs), vitamin E, vitamin C, vitamin E, CoQ10, polyphenols, chlorophyll, zeaxanthin, polyunsaturated fatty acids, eicosapentaenoic acid, docosahexaenoic acid, alpha-linolenic acid, and monounsaturated fatty acids . Inclusion criteria included the above stated keywords and access to full text. RESULTS: A WFPB diet maximizes the antioxidant potential within our cells by providing essential vitamins, including vitamins A, C, and E. It also helps to eliminate harmful carcinogens and gerontotoxins within our bloodstream and has been shown to lengthen telomeres, which prevents cellular damage. CONCLUSION: Evidence obtained within this literature review supports a WFPB diet for preventing skin aging. ., Competing Interests: FUNDING:No funding was provided for this study. DISCLOSURES:The authors have no conflicts of interest relevant to the content of this article., (Copyright © 2020. Matrix Medical Communications. All rights reserved.)

In asthma, acute bronchospasm is driven by contractile forces of airway smooth muscle (ASM). These forces can be imaged in the cultured ASM cell or assessed in the muscle strip and the tracheal/bronchial ring, but in each case, the ASM is studied in isolation from the native airway milieu. Here, we introduce a novel platform called tissue traction microscopy (TTM) to measure ASM contractile force within porcine and human precision-cut lung slices (PCLS). Compared with the conventional measurements of lumen area changes in PCLS, TTM measurements of ASM force changes are 1 ) more sensitive to bronchoconstrictor stimuli, 2 ) less variable across airways, and 3 ) provide spatial information. Notably, within every human airway, TTM measurements revealed local regions of high ASM contraction that we call "stress hotspots". As an acute response to cyclic stretch, these hotspots promptly decreased but eventually recovered in magnitude, spatial location, and orientation, consistent with local ASM fluidization and resolidification. By enabling direct and precise measurements of ASM force, TTM should accelerate preclinical studies of airway reactivity.

Background: The relationship between asthma, atopy, and underlying type 2 (T2) airway inflammation is complex. Although the bacterial airway microbiota is known to differ in asthmatic patients, the fungal and bacterial markers that discriminate T2-high (eosinophilic) and T2-low (neutrophilic/mixed-inflammation) asthma and atopy are still incompletely identified., Objectives: The aim of this study was to demonstrate the fungal microbiota structure of airways in asthmatic patients associated with T2 inflammation, atopy, and key clinical parameters., Methods: We collected endobronchial brush (EB) and bronchoalveolar lavage (BAL) samples from 39 asthmatic patients and 19 healthy subjects followed by 16S gene and internal transcribed spacer-based microbiota sequencing. The microbial sequences were classified into exact sequence variants. The T2 phenotype was defined by using a blood eosinophil count with a threshold of 300 cells/μL., Results: Fungal diversity was significantly lower in EB samples from patients with T2-high compared with T2-low inflammation; key fungal genera enriched in patients with T2-high inflammation included Trichoderma species, whereas Penicillium species was enriched in patients with atopy. In BAL fluid samples the dominant genera were Cladosporium, Fusarium, Aspergillus, and Alternaria. Using generalized linear models, we identified significant associations between specific fungal exact sequence variants and FEV 1 , fraction of exhaled nitric oxide values, BAL fluid cell counts, and corticosteroid use. Investigation of interkingdom (bacterial-fungal) co-occurrence patterns revealed different topologies between asthmatic patients and healthy control subjects. Random forest models with fungal classifiers predicted asthma status with 75% accuracy for BAL fluid samples and 80% accuracy for EB samples., Conclusions: We demonstrate clear differences in bacterial and fungal microbiota in asthma-associated phenotypes. Our study provides additional support for considering microbial signatures in delineating asthma phenotypes., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Morbidity from asthma is disproportionately higher among black patients than among white patients, and black patients constitute the minority of participants in trials informing treatment. Data indicate that patients with inadequately controlled asthma benefit more from addition of a long-acting beta-agonist (LABA) than from increased glucocorticoids; however, these data may not be informative for treatment in black patients., Methods: We conducted two prospective, randomized, double-blind trials: one involving children and the other involving adolescents and adults. In both trials, the patients had at least one grandparent who identified as black and had asthma that was inadequately controlled with low-dose inhaled glucocorticoids. We compared combinations of therapy, which included the addition of a LABA (salmeterol) to an inhaled glucocorticoid (fluticasone propionate), a step-up to double to quintuple the dose of fluticasone, or both. The treatments were compared with the use of a composite measure that evaluated asthma exacerbations, asthma-control days, and lung function; data were stratified according to genotypic African ancestry., Results: When quintupling the dose of fluticasone (to 250 μg twice a day) was compared with adding salmeterol (50 μg twice a day) and doubling the fluticasone (to 100 μg twice a day), a superior response occurred in 46% of the children with quintupling the fluticasone and in 46% of the children with doubling the fluticasone and adding salmeterol (P = 0.99). In contrast, more adolescents and adults had a superior response to added salmeterol than to an increase in fluticasone (salmeterol-low-dose fluticasone vs. medium-dose fluticasone, 49% vs. 28% [P = 0.003]; salmeterol-medium-dose fluticasone vs. high-dose fluticasone, 49% vs. 31% [P = 0.02]). Neither the degree of African ancestry nor baseline biomarkers predicted a superior response to specific treatments. The increased dose of inhaled glucocorticoids was associated with a decrease in the ratio of urinary cortisol to creatinine in children younger than 8 years of age., Conclusions: In contrast to black adolescents and adults, almost half the black children with poorly controlled asthma had a superior response to an increase in the dose of an inhaled glucocorticoid and almost half had a superior response to the addition of a LABA. (Funded by the National Heart, Lung, and Blood Institute; BARD ClinicalTrials.gov number, NCT01967173.)., (Copyright © 2019 Massachusetts Medical Society.)

Background: Loss of bronchoprotection (LOBP) with a regularly used long-acting β 2 -adrenergic receptor agonist (LABA) is well documented. LOBP has been attributed to β 2 -adrenergic receptor (B2AR) downregulation, a process requiring farnesylation, which is inhibited by alendronate., Objective: We sought to determine whether alendronate can reduce LABA-associated LOBP in inhaled corticosteroid (ICS)-treated patients., Methods: We conducted a randomized, double-blind, placebo-controlled, parallel-design, proof-of-concept trial. Seventy-eight participants with persistent asthma receiving 250 μg of fluticasone twice daily for 2 weeks were randomized to receive alendronate or placebo while initiating salmeterol for 8 weeks. Salmeterol-protected methacholine challenges (SPMChs) and PBMC B2AR numbers (radioligand binding assay) and signaling (cyclic AMP ELISA) were assessed before randomization and after 8 weeks of ICS plus LABA treatment. LOBP was defined as a more than 1 doubling dose reduction in SPMCh PC 20 value., Results: The mean doubling dose reduction in SPMCh PC 20 value was 0.50 and 0.27 with alendronate and placebo, respectively (P = .62). Thirty-eight percent of participants receiving alendronate and 33% receiving placebo had LOBP (P = .81). The after/before ICS plus LABA treatment ratio of B2AR number was 1.0 for alendronate (P = .86) and 0.8 for placebo (P = .15; P = .31 for difference between treatments). The B2AR signaling ratio was 0.89 for alendronate (P = .43) and 1.02 for placebo (P = .84; P = .44 for difference). Changes in lung function and B2AR number and signaling were similar between those who did and did not experience LOBP., Conclusion: This study did not find evidence that alendronate reduces LABA-associated LOBP, which relates to the occurrence of LOBP in only one third of participants. LOBP appears to be less common than presumed in concomitant ICS plus LABA-treated asthmatic patients. B2AR downregulation measured in PBMCs does not appear to reflect LOBP., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective: The study sought to implement and assess the CommunityRx e-prescribing system to recruit research participants from a predominantly non-Hispanic Black community on Chicago's South Side., Materials and Methods: CommunityRx integrates with electronic medical record systems to generate a personalized list of health-promoting community resources (HealtheRx). Between December 2015 and December 2016, HealtheRxs distributed at outpatient visits to adults with asthma or chronic obstructive pulmonary disease also incentivized participation in a pulmonary research registry. Usual practices for registry recruitment continued in parallel., Results: Focus groups established acceptability and appropriateness among the target population. Pulmonary research registry recruitment information was included on 13 437 HealtheRxs. Forty-one (90% non-Hispanic Black) patients responded with willingness to participate and 9 (8 non-Hispanic Black) returned a signed consent required to enroll. Usual recruitment practices enrolled 4 registrants (1 non-Hispanic Black)., Discussion: Automating research recruitment using a community e-prescribing system is feasible., Conclusions: Implementation of an electronic medical record-integrated, community resource referral tool promotes enrollment of eligible underrepresented research participants; however, enrollment was low., (© The Author(s) 2019. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)